Nucleoside phosphoramidate prodrugs

ABSTRACT

Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: 
     
       
         
         
             
             
         
       
     
     Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.

FIELD OF INVENTION

The present invention pertains to nucleoside phosphoramidates and theiruse as agents for treating viral diseases. These compounds areinhibitors of RNA-dependent RNA viral replication and are useful asinhibitors of HCV NS5B polymerase, as inhibitors of HCV replication andfor treatment of hepatitis C infection in mammals. The inventionprovides novel chemical compounds, and the use of these compounds aloneor in combination with other antiviral agents for treating HCVinfection.

BACKGROUND

Hepatitis C virus (HCV) infection is a major health problem that leadsto chronic liver disease, such as cirrhosis and hepatocellularcarcinoma, in a substantial number of infected individuals, estimated tobe 2-15% of the world's population. There are an estimated 4.5 millioninfected people in the United States alone, according to the U.S. Centerfor Disease Control. According to the World Health Organization, thereare more than 200 million infected individuals worldwide, with at least3 to 4 million people being infected each year. Once infected, about 20%of people clear the virus, but the rest can harbor HCV the rest of theirlives. Ten to twenty percent of chronically infected individualseventually develop liver-destroying cirrhosis or cancer. The viraldisease is transmitted parenterally by contaminated blood and bloodproducts, contaminated needles, or sexually and vertically from infectedmothers or carrier mothers to their offspring. Current treatments forHCV infection, which are restricted to immunotherapy with recombinantinterferon-α alone or in combination with the nucleoside analogribavirin, are of limited clinical benefit. Moreover, there is noestablished vaccine for HCV. Consequently, there is an urgent need forimproved therapeutic agents that effectively combat chronic HCVinfection.

The HCV virion is an enveloped positive-strand RNA virus with a singleoligoribonucleotide genomic sequence of about 9600 bases which encodes apolyprotein of about 3,010 amino acids. The protein products of the HCVgene consist of the structural proteins C, E1, and E2, and thenon-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. Thenonstructural (NS) proteins are believed to provide the catalyticmachinery for viral replication. The NS3 protease releases NS5B, theRNA-dependent RNA polymerase from the polyprotein chain. HCV NS5Bpolymerase is required for the synthesis of a double-stranded RNA from asingle-stranded viral RNA that serves as a template in the replicationcycle of HCV. Therefore, NS5B polymerase is considered to be anessential component in the HCV replication complex (K. Ishi, et al,Heptology, 1999, 29: 1227-1235; V. Lohmann, et al., Virology, 1998, 249:108-118). Inhibition of HCV NS5B polymerase prevents formation of thedouble-stranded HCV RNA and therefore constitutes an attractive approachto the development of HCV-specific antiviral therapies.

HCV belongs to a much larger family of viruses that share many commonfeatures.

Flaviviridae Viruses

The Flaviviridae family of viruses comprises at least three distinctgenera: pestiviruses, which cause disease in cattle and pigs;flavivruses, which are the primary cause of diseases such as denguefever and yellow fever; and hepaciviruses, whose sole member is HCV. Theflavivirus genus includes more than 68 members separated into groups onthe basis of serological relatedness (Calisher et al., J. Gen. Virol,1993, 70,37-43). Clinical symptoms vary and include fever, encephalitisand hemorrhagic fever (Fields Virology, Editors: Fields, B. N., Knipe,D. M., and Howley, P. M., Lippincott-Raven Publishers, Philadelphia,Pa., 1996, Chapter 31, 931-959). Flaviviruses of global concern that areassociated with human disease include the Dengue Hemorrhagic Feverviruses (DHF), yellow fever virus, shock syndrome and Japaneseencephalitis virus (Halstead, S. B., Rev. Infect. Dis., 1984, 6,251-264; Halstead, S. B., Science, 239:476-481, 1988; Monath, T. P., NewEng. J. Med, 1988, 319, 64 1-643).

The pestivirus genus includes bovine viral diarrhea virus (BVDV),classical swine fever virus (CSFV, also called hog cholera virus) andborder disease virus (BDV) of sheep (Moennig, V. et al. Adv. Vir. Res.1992, 41, 53-98). Pestivirus infections of domesticated livestock(cattle, pigs and sheep) cause significant economic losses worldwide.BVDV causes mucosal disease in cattle and is of significant economicimportance to the livestock industry (Meyers, G. and Thiel, H. J.,Advances in Virus Research, 1996, 47, 53-118; Moennig V., et al, Adv.Vir. Res. 1992, 41, 53-98). Human pestiviruses have not been asextensively characterized as the animal pestiviruses. However,serological surveys indicate considerable pestivirus exposure in humans.

Pestiviruses and hepaciviruses are closely related virus groups withinthe Flaviviridae family. Other closely related viruses in this familyinclude the GB virus A, GB virus A-like agents, GB virus-B and GBvirus-C (also called hepatitis G virus, HGV). The hepacivirus group(hepatitis C virus; HCV) consists of a number of closely related butgenotypically distinguishable viruses that infect humans. There are atleast 6 HCV genotypes and more than 50 subtypes. Due to the similaritiesbetween pestiviruses and hepaciviruses, combined with the poor abilityof hepaciviruses to grow efficiently in cell culture, bovine viraldiarrhea virus (BVDV) is often used as a surrogate to study the HCVvirus.

The genetic organization of pestiviruses and hepaciviruses is verysimilar. These positive stranded RNA viruses possess a single large openreading frame (ORF) encoding all the viral proteins necessary for virusreplication. These proteins are expressed as a polyprotein that is co-and post-translationally processed by both cellular and virus-encodedproteinases to yield the mature viral proteins. The viral proteinsresponsible for the replication of the viral genome RNA are locatedwithin approximately the carboxy-terminal. Two-thirds of the ORF aretermed nonstructural (NS) proteins. The genetic organization andpolyprotein processing of the nonstructural protein portion of the ORFfor pestiviruses and hepaciviruses is very similar. For both thepestiviruses and hepaciviruses, the mature nonstructural (NS) proteins,in sequential order from the amino-terminus of the nonstructural proteincoding region to the carboxy-terminus of the ORF, consist of p7, NS2,NS3, NS4A, NS4B, NS5A, and NS5B.

The NS proteins of pestiviruses and hepaciviruses share sequence domainsthat are characteristic of specific protein functions. For example, theNS3 proteins of viruses in both groups possess amino acid sequencemotifs characteristic of serine proteinases and of helicases (Gorbalenyaet al., Nature, 1988, 333, 22; Bazan and Fletterick Virology, 1989,171,637-639; Gorbalenya et al., Nucleic Acid Res., 1989, 17, 3889-3897).Similarly, the NS5B proteins of pestiviruses and hepaciviruses have themotifs characteristic of RNA-directed RNA polymerases (Koonin, E. V. andDolja, V. V., Crir. Rev. Biochem. Molec. Biol. 1993, 28, 375-430).

The actual roles and functions of the NS proteins of pestiviruses andhepaciviruses in the lifecycle of the viruses are directly analogous. Inboth cases, the NS3 serine proteinase is responsible for all proteolyticprocessing of polyprotein precursors downstream of its position in theORF (Wiskerchen and Collett, Virology, 1991, 184, 341-350;Bartenschlager et al., J. Virol. 1993, 67, 3835-3844; Eckart et al.Biochem. Biophys. Res. Comm. 1993, 192,399-406; Grakoui et al., J.Virol. 1993, 67, 2832-2843; Grakoui et al., Proc. Natl. Acad. Sci. USA1993, 90, 10583-10587; Hijikata et al., J. Virol. 1993, 67, 4665-4675;Tome et al., J. Virol., 1993, 67, 4017-4026). The NS4A protein, in bothcases, acts as a cofactor with the NS3 serine protease (Bartenschlageret al., J. Virol. 1994, 68, 5045-5055; Failla et al., J. Virol. 1994,68, 3753-3760; Xu et al., J. Virol., 1997, 71:53 12-5322). The NS3protein of both viruses also functions as a helicase (Kim et al.,Biochem. Biophys. Res. Comm., 1995, 215, 160-166; Jin and Peterson,Arch. Biochem. Biophys., 1995, 323, 47-53; Warrener and Collett, J.Virol. 1995, 69,1720-1726). Finally, the NS5B proteins of pestivirusesand hepaciviruses have the predicted RNA-directed RNA polymerasesactivity (Behrens et al., EMBO, 1996, 15, 12-22; Lechmann et al., J.Virol., 1997, 71, 8416-8428; Yuan et al., Biochem. Biophys. Res. Comm.1997, 232, 231-235; Hagedorn, PCT WO 97/12033; Zhong et al, J. Virol.,1998, 72, 9365-9369).

Currently, there are limited treatment options for individuals infectedwith hepatitis C virus. The current approved therapeutic option is theuse of immunotherapy with recombinant interferon-α alone or incombination with the nucleoside analog ribavirin. This therapy islimited in its clinical effectiveness and only 50% of treated patientsrespond to therapy. Therefore, there is significant need for moreeffective and novel therapies to address the unmet medical need posed byHCV infection.

A number of potential molecular targets for drug development of directacting antivirals as anti-HCV therapeutics have now been identifiedincluding, but not limited to, the NS2-NS3 autoprotease, the N3protease, the N3 helicase and the NS5B polymerase. The RNA-dependent RNApolymerase is absolutely essential for replication of thesingle-stranded, positive sense, RNA genome and this enzyme has elicitedsignificant interest among medicinal chemists.

Inhibitors of HCV NS5B as potential therapies for HCV infection havebeen reviewed: Tan, S.-L., et al., Nature Rev. Drug Discov., 2002, 1,867-881; Walker, M. P. et al., Exp. Opin. Investigational Drugs, 2003,12, 1269-1280; Ni, Z-J., et al., Current Opinion in Drug Discovery andDevelopment, 2004, 7, 446-459; Beaulieu, P. L., et al., Current Opinionin Investigational Drugs, 2004, 5, 838-850; Wu, J., et al., Current DrugTargets-Infectious Disorders, 2003, 3, 207-219; Griffith, R. C., et al,Annual Reports in Medicinal Chemistry, 2004, 39, 223-237; Carrol, S., etal., Infectious Disorders-Drug Targets, 2006, 6, 17-29. The potentialfor the emergence of resistant HCV strains and the need to identifyagents with broad genotype coverage supports the need for continuingefforts to identify novel and more effective nucleosides as HCV NS5Binhibitors.

Nucleoside inhibitors of NS5B polymerase can act either as a non-naturalsubstrate that results in chain termination or as a competitiveinhibitor which competes with nucleotide binding to the polymerase. Tofunction as a chain terminator the nucleoside analog must be taken up bythe cell and converted in vivo to a triphosphate to compete for thepolymerase nucleotide binding site. This conversion to the triphosphateis commonly mediated by cellular kinases which imparts additionalstructural requirements on a potential nucleoside polymerase inhibitor.Unfortunately, this limits the direct evaluation of nucleosides asinhibitors of HCV replication to cell-based assays capable of in situphosphorylation.

In some cases, the biological activity of a nucleoside is hampered byits poor substrate characteristics for one or more of the kinases neededto convert it to the active triphosphate form. Formation of themonophosphate by a nucleoside kinase is generally viewed as the ratelimiting step of the three phosphorylation events. To circumvent theneed for the initial phosphorylation step in the metabolism of anucleoside to the active triphosphate analog, the preparation of stablephosphate prodrugs has been reported. Nucleoside phosphoramidateprodrugs have been shown to be precursors of the active nucleosidetriphosphate and to inhibit viral replication when administered to viralinfected whole cells (McGuigan, C., et al., J. Med. Chem., 1996, 39,1748-1753; Valette, G., et al., J. Med. Chem., 1996, 39, 1981-1990;Balzarini, J., et al., Proc. National Acad Sci USA, 1996, 93, 7295-7299;Siddiqui, A. Q., et al., J. Med. Chem., 1999, 42, 4122-4128; Eisenberg,E. J., et al., Nucleosides, Nucleotides and Nucleic Acids, 2001, 20,1091-1098; Lee, W. A., et al., Antimicrobial Agents and Chemotherapy,2005, 49, 1898); US 20060241064; and WO 2007095269.

Also limiting the utility of nucleosides as viable therapeutic agents istheir sometimes poor physicochemical and pharmacokinetic properties.These poor properties can limit the intestinal absorption of an agentand limit uptake into the target tissue or cell. To improve on theirproperties prodrugs of nucleosides have been employed. It has beendemonstrated that preparation of nucleoside phosphoramidates improvesthe systemic absorption of a nucleoside and furthermore, thephosphoramidate moiety of these “pronucleotides” is masked with neutrallipophilic groups to obtain a suitable partition coefficient to optimizeuptake and transport into the cell dramatically enhancing theintracellular concentration of the nucleoside monophosphate analogrelative to administering the parent nucleoside alone. Enzyme-mediatedhydrolysis of the phosphate ester moiety produces a nucleosidemonophosphate wherein the rate limiting initial phosphorylation isunnecessary.

SUMMARY OF THE INVENTION

The present invention is directed toward novel phosphoramidate prodrugsof nucleoside derivatives for the treatment of viral infections inmammals, which is a compound, its stereoisomers, salts (acid or basicaddition salts), hydrates, solvates, or crystalline forms thereof,represented by the following structure:

-   -   wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is OR′ or —N(R^(1′))₂);

(b) R² is hydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), andR^(3b);

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C₁₋₁₀haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl,substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),alkyl)₂, N(C₁₋₄ acyl)₂;

the base is a naturally occurring or modified purine or pyrimidine baserepresented by the following structures:

-   -   wherein

Z is N or CR¹²;

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F, Cl, Br, I, OH, OR′, SH,SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I)lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkenyl of C₂-C₆, lower alkynyl of C₂-C₆ such as C≡CH, halogenated(F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆,halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂,CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is an optionally substituted alkyl, which includes, but isnot limited to, an optionally substituted C₁₋₂₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted lower alkyl; anoptionally substituted cycloalkyl; an optionally substituted alkynyl ofC₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, or optionallysubstituted acyl, which includes but is not limited to C(O)alkyl,C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

R¹² is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′,NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkylof C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H,or CH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.

DEFINITIONS

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the first definitionprovided in the Summary of the Invention

The terms “optional” or “optionally” as used herein means that asubsequently described event or circumstance may but need not occur, andthat the description includes instances where the event or circumstanceoccurs and instances in which it does not. For example, “optional bond”means that the bond may or may not be present, and that the descriptionincludes single, double, or triple bonds.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R appears twice and is defined as“independently carbon or nitrogen”, both R's can be carbon, both R's canbe nitrogen, or one R′ can be carbon and the other nitrogen.

The term “alkenyl” refers to an unsubstituted hydrocarbon chain radicalhaving from 2 to 10 carbon atoms having one or two olefinic doublebonds, preferably one olefinic double bond. The term “C_(2-N) alkenyl”refers to an alkenyl comprising 2 to N carbon atoms, where N is aninteger having the following values: 3, 4, 5, 6, 7, 8, 9, or 10. Theterm “C₂₋₁₀ alkenyl” refers to an alkenyl comprising 2 to 10 carbonatoms. The term “C₂₋₄ alkenyl” refers to an alkenyl comprising 2 to 4carbon atoms. Examples include, but are not limited to, vinyl,1-propenyl, 2-propenyl(allyl) or 2-butenyl (crotyl).

The term “halogenated alkenyl” refers to an alkenyl comprising at leastone of F, Cl, Br, and I.

The term “alkyl” refers to an unbranched or branched chain, saturated,monovalent hydrocarbon residue containing 1 to 30 carbon atoms. The term“C_(1-M) alkyl” refers to an alkyl comprising 1 to M carbon atoms, whereM is an integer having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, or 30. The term “C₁₋₄ alkyl” refers to an alkyl containing 1 to 4carbon atoms. The term “lower alkyl” denotes a straight or branchedchain hydrocarbon residue comprising 1 to 6 carbon atoms. “C₁₋₂₀ alkyl”as used herein refers to an alkyl comprising 1 to 20 carbon atoms.“C₁₋₁₀ alkyl” as used herein refers to an alkyl comprising 1 to 10carbons. Examples of alkyl groups include, but are not limited to, loweralkyl groups include methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,t-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. Theterm (ar)alkyl or (heteroaryl)alkyl indicate the alkyl group isoptionally substituted by an aryl or a heteroaryl group respectively.

The term “cycloalkyl” refers to an unsubstituted or substitutedcarbocycle, in which the carbocycle contains 3 to 10 carbon atoms;preferably 3 to 8 carbon atoms; more preferably 3 to 6 carbon atoms(i.e., lower cycloalkyls). Examples of cycloalkyl groups include, butare not limited to, cyclopropyl, 2-methyl-cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

The term “cycloalkyl alkyl” refers to an additionally unsubstituted orsubstituted alkyl substituted by a lower cycloalkyl. Examples ofcycloalkyl alkyls include, but are not limited to, any one of methyl,ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl, isopentyl,neopentyl, hexyl, heptyl, and octyl that is substituted withcyclopropyl, 2-methyl-cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “cycloheteroalkyl” refers to an unsubstituted or substitutedheterocycle, in which the heterocycle contains 2 to 9 carbon atoms;preferably 2 to 7 carbon atoms; more preferably 2 to 5 carbon atoms.Examples of cycloheteroalkyls include, but are not limited to,aziridin-2-yl, N—C₁₋₃-alkyl-aziridin-2-yl, azetidinyl,N—C₁₋₃-alkyl-azetidin-m′-yl, pyrrolidin-m′-yl,N—C₁₋₃-alkyl-pyrrolidin-m′-yl, piperidin-m′-yl, andN—C₁₋₃-alkyl-piperidin-m′-yl, where m′ is 2, 3, or 4 depending on thecycloheteroalkyl. Specific examples of N—C₁₋₃-alkyl-cycloheteroalkylsinclude, but are not limited to, N-methyl-aziridin-2-yl,N-methyl-azetidin-3-yl, N-methyl-pyrrolidin-3-yl,N-methyl-pyrrolidin-4-yl, N-methyl-piperidin-2-yl,N-methyl-piperidin-3-yl, and N-methyl-piperidin-4-yl. In the instance ofR⁴, the point of attachment between the cycloheteroalkyl ring carbon andthe oxygen occurs at any one of m′

The term “heterocycle” refers to an unsubstituted or substitutedheterocycle containing carbon, hydrogen, and at least one of N, O, andS, where the C and N can be trivalent or tetravalent, i.e., sp²- orsp³-hybridized. Examples of heterocycles include, but are not limitedto, aziridine, azetidine, pyrrolidine, piperidine, imidazole, oxazole,piperazine, etc. In the instance of piperazine, as related to R¹⁰ forNR′₂, the corresponding opposite nitrogen atom of the piperazinyl issubstituted by a lower alkyl represented by the following structure:

Preferably, the opposite nitrogen of the piperazinyl is substituted by amethyl group.

The term “halogenated alkyl” (or “haloalkyl”) refers to an unbranched orbranched chain alkyl comprising at least one of F, Cl, Br, and I. Theterm “C_(1-M) haloalkyl” refers to an alkyl comprising 1 to M carbonatoms that comprises at least one of F, Cl, Br, and I, where M is aninteger having the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or30. “C₁₋₃ haloalkyl” refers to a haloalkyl comprising 1 to 3 carbons andat least one of F, Cl, Br, and I. The term “halogenated lower alkyl” (or“lower haloalkyl”) refers to a haloalkyl comprising 1 to 6 carbon atomsand at least one of F, Cl, Br, and I. Examples include, but are notlimited to, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,difluoromethyl, dichloromethyl, dibromomethyl, diiodomethyl,trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl,1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl,2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl,2,2-dichloroethyl, 2,2-dibromomethyl, 2-2-diiodomethyl, 3-fluoropropyl,3-chloropropyl, 3-bromopropyl, 2,2,2-trifluoroethyl or1,1,2,2,2-pentafluoroethyl.

The term “alkynyl” refers to an unbranched or branched hydrocarbon chainradical having from 2 to 10 carbon atoms, preferably 2 to 5 carbonatoms, and having one triple bond. The term “C_(2-N) alkynyl” refers toan alkynyl comprising 2 to N carbon atoms, where N is an integer havingthe following values: 3, 4, 5, 6, 7, 8, 9, or 10. The term “C C₂₋₄alkynyl” refers to an alkynyl comprising 2 to 4 carbon atoms. The term“C₂₋₁₀ alkynyl” refers to an alkynyl comprising 2 to 10 carbons.Examples include, but are limited to, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl or 3-butynyl.

The term “halogenated alkynyl” refers to an unbranched or branchedhydrocarbon chain radical having from 2 to 10 carbon atoms, preferably 2to 5 carbon atoms, and having one triple bond and at least one of F, Cl,Br, and I.

The term “cycloalkyl” refers to a saturated carbocyclic ring comprising3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or cyclooctyl. The term “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl comprising 3 to 7 carbons in thecarbocyclic ring.

The term “alkoxy” refers to an —O-alkyl group or an —O-cycloalkyl group,wherein alkyl and cycloalkyl are as defined above. Examples of —O-alkylgroups include, but are not limited to, methoxy, ethoxy, n-propyloxy,i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy. “Lower alkoxy” as usedherein denotes an alkoxy group with a “lower alkyl” group as previouslydefined. “C₁₋₁₀ alkoxy” refers to an-O-alkyl wherein alkyl is C₁₋₁₀.Examples of —O-cycloalkyl groups include, but are not limited to,—O-c-propyl, —O-c-butyl, —O-c-pentyl, and —O-c-hexyl.

The term “halogenated alkoxy” refers to an —O-alkyl group in which thealkyl group comprises at least one of F, Cl, Br, and I.

The term “halogenated lower alkoxy” refers to an —O-(lower alkyl) groupin which the lower alkyl group comprises at least one of F, Cl, Br, andI.

The term “amino acid” includes naturally occurring and synthetic α, βγor δ amino acids, and includes but is not limited to, amino acids foundin proteins, i.e. glycine, alanine, valine, leucine, isoleucine,methionine, phenylalanine, tryptophan, proline, serine, threonine,cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine,arginine and histidine. In a preferred embodiment, the amino acid is inthe L-configuration. Alternatively, the amino acid can be a derivativeof alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl,tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl,tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl,argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl,β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl,β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl,β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-argininyl orβ-histidinyl. When the term amino acid is used, it is considered to be aspecific and independent disclosure of each of the esters of α, βγ or δglycine, alanine, valine, leucine, isoleucine, methionine,phenylalanine, tryptophan, proline, serine, threonine, cysteine,tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginineand histidine in the D and L-configurations.

The term “aminoacyl” includes N,N-unsubstituted, N,N-monosubstituted,and N,N-disubstituted derivatives of naturally occurring and syntheticα, βγ or δ amino acyls, where the amino acyls are derived from aminoacids. The amino-nitrogen can be substituted or unsubstituted. When theamino-nitrogen is substituted, the nitrogen is either mono- ordi-substituted, where the substituent bound to the amino-nitrogen is alower alkyl or an alkaryl. In the instance of its use for Y, theexpression “O(aminoacyl)” is used. It is understood that the C3′ carbonof the ribose is bound to the oxygen “O”, which is then bound to thecarbonyl carbon of the aminoacyl.

The terms “alkylamino” or “arylamino” refer to an amino group that hasone or two alkyl or aryl substituents, respectively.

The term “protected,” as used herein and unless otherwise defined,refers to a group that is added to an oxygen, nitrogen, or phosphorusatom to prevent its further reaction or for other purposes. A widevariety of oxygen and nitrogen protecting groups are known to thoseskilled in the art of organic synthesis. Non-limiting examples include:C(O)-alkyl, C(O)Ph, C(O)aryl, CH₃, CH₂-alkyl, CH₂-alkenyl, CH₂Ph,CH₂-aryl, CH₂O-alkyl, CH₂O-aryl, SO₂-alkyl, SO₂-aryl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene).

The term “aryl,” as used herein, and unless otherwise specified, refersto substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl,preferably the term aryl refers to substituted or unsubstituted phenyl.The aryl group can be substituted with one or more moieties selectedfrom among hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy,aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid,phosphate, and phosphonate, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 3rd ed., John Wiley & Sons, 1999.

The terms “alkaryl” or “alkylaryl” refer to an alkyl group with an arylsubstituent, such as benzyl. The terms “aralkyl” or “arylalkyl” refer toan aryl group with an alkyl substituent.

The term “di(lower alkyl)amino-lower alkyl” refers to a lower alkylsubstituted by an amino group that is itself substituted by two loweralkyl groups. Examples include, but are not limited to, (CH₃)₂NCH₂,(CH₃)₂NCH₂CH₂, (CH₃)₂NCH₂CH₂CH₂, etc. The examples above show loweralkyls substituted at the terminus carbon atom with anN,N-dimethyl-amino substituent. These are intended as examples only andare not intended to limit the meaning of the term “di(loweralkyl)amino-lower alkyl” so as to require the same. It is contemplatedthat the lower alkyl chain can be substituted with an N,N-di(loweralkyl)-amino at any point along the chain, e.g., CH₃CH(N-(loweralkyl)₂)CH₂CH₂.

The term “halo,” as used herein, includes chloro, bromo, iodo andfluoro.

The term “acyl” refers to a substituent containing a carbonyl moiety anda non-carbonyl moiety. The carbonyl moiety contains a double-bondbetween the carbonyl carbon and a heteroatom, where the heteroatom isselected from among O, N and S. When the heteroatom is N, the N issubstituted by a lower alkyl. The non-carbonyl moiety is selected fromstraight, branched, and cyclic alkyl, which includes, but is not limitedto, a straight, branched, or cyclic C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or loweralkyl; alkoxyalkyl, including methoxymethyl; aralkyl, including benzyl;aryloxyalkyl, such as phenoxymethyl; or aryl, including phenyloptionally substituted with halogen (F, Cl, Br, I), hydroxyl, C₁ to C₄alkyl, or C₁ to C₄ alkoxy, sulfonate esters, such as alkyl or aralkylsulphonyl, including methanesulfonyl, the mono, di or triphosphateester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl(e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl. When at least onearyl group is present in the non-carbonyl moiety, it is preferred thatthe aryl group comprises a phenyl group.

The term “lower acyl” refers to an acyl group in which the non-carbonylmoiety is lower alkyl.

The term “purine” or “pyrimidine” base includes, but is not limited to,adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl,aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine,N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkylpurine, N⁶-allcylaminopurine, N⁶-thioallyl purine, N²-alkylpurines,N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine,5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil,C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines,C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine,C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine,C⁵-iodopyrimidine, C⁶-lodo-pyrimidine, C⁵—Br-vinyl pyrimidine,C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine,N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl,triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, andpyrazolopyrimidinyl. Purine bases include, but are not limited to,guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.Functional oxygen and nitrogen groups on the base can be protected asnecessary or desired. Suitable protecting groups are well known to thoseskilled in the art, and include trimethylsilyl, dimethylhexylsilyl,t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups,and acyl groups such as acetyl and propionyl, methanesulfonyl, andp-toluenesulfonyl.

The term “tautomerism” and “tautomers” have their accepted plainmeanings.

The term “P*” means that the phosphorous atom is chiral and that it hasa corresponding Cahn-Ingold-Prelog designation of “R” or “S” which havetheir accepted plain meanings. It is contemplated that compounds of theformula I are racemic because the chirality at phosphorous. Applicantscontemplate use of the racemate and/or the resolved enantiomers. In someinstances, an asterisk does not appear next to the phosphoroamidatephosphorous atom. In these instances, it is understood that thephosphorous atom is chiral and that one of ordinary skill understandsthis to be so unless the substituents bound to the phosphorous excludethe possibility of chirality at phosphorous, such as in P(O)Cl₃.

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the invention is directed to a compound, its salts,hydrates, solvates, crystalline forms, and the like represented byformula I:

-   -   wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is OR′ or —N(R^(1′))₂);

(b) R² is hydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), andR^(3b);

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂) so as to form a cyclic ring that includes theadjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, fis 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogen orC₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C₁₋₁₀haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl,substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

the base is a naturally occurring or modified purine or pyrimidine baserepresented by the following structures:

-   -   wherein

Z is N or CR¹²;

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F, Cl, Br, I, OH, OR′, SH,SR′, NH₂, NHR′, NR′₁₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I)lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkenyl of C₂-C₆, lower alkynyl of C₂-C₆ such as C≡CH, halogenated(F, Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆,halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂,CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is an optionally substituted alkyl, which includes, but isnot limited to, an optionally substituted C₁₋₂₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted lower alkyl; anoptionally substituted cycloalkyl; an optionally substituted alkynyl ofC₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, or optionallysubstituted acyl, which includes but is not limited to C(O)alkyl,C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

R¹² is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′,NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkylof C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H,or CH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.

As can be appreciated from the structure represented by formula I above,there are myriad ways to express the several embodiments and aspects ofeach embodiment of the present invention. As seen below, the inventorshave disclosed certain embodiments directed to the compound of formulaI, each having several aspects, based on the identity of the modifiedpurine or pyrimidine base. This is not intended to be an explicit orimplicit admission that the three embodiments are independent ordistinct nor should it be interpreted as such. Rather, it is intended toconvey information so that the full breadth of the present invention canbe understood. Furthermore, the following embodiments, and aspectsthereof, are not meant to be limiting on the full breadth of theinvention as recited by the structure of formula I.

A first embodiment of the invention is directed to a compoundrepresented by formula I-1:

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are(CH₂)_(n) so as to form a cyclic ring that includes the adjoining N andC atoms, C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), andR^(3b);

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C₁₋₁₀haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aminoacyl, di(lower alkyl)-amino, aryl, such as phenyl, heteroaryl, suchas, pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R⁷, R⁸, R⁹ are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, loweralkenyl of C₂-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, wherein R′ is aC₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆ alkynyl.

A first aspect of the first embodiment is directed to a compoundrepresented by formula I-1

wherein

(a) R¹ is hydrogen, n-alkyl or aryl, which includes, but is not limitedto, phenyl or naphthyl, where phenyl or naphthyl are optionallysubstituted with at least one of C₁₋₆ alkyl, C₁₋₆ alkoxy, F, Cl, Br, I,nitro, cyano, C₁₋₆ haloalkyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are independently (i) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 3 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), or CH₂SH and R^(3b) is H;

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy, di(lower alkyl)-amino, or halogen, C₁₋₁₀haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkyl alkyl, cycloheteroalkyl,aminoacyl, aryl, such as phenyl, heteroaryl, such as, pyridinyl,substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, CN, CH₃, vinyl, OCH₃, OCH₂CH₃, CH₂OH, CH₂(halo), such asCH₂F, N₃, CH₂CN, CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, includingF, Cl, Br, or I, with the provisos that when X is OH, base is cytosineand R⁶ is H, R⁵ cannot be N3;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, vinyl, N₃, CN, Cl, Br, F, I, O(C₁₋₆ acyl),O(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl),NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl,alkenyl and vinyl are optionally substituted by N₃, CN, one to threehalogen (Cl, Br, F, I), NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl),OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₄ haloalkyl,O(aminoacyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl),SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl),SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl),NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, orN(C₁₋₄ acyl)₂;

(i) R⁷, R⁸, R⁹ are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, loweralkenyl of C₂-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, wherein R′ is aC₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆ alkynyl.

A second aspect of the first embodiment is directed to a compoundrepresented by formula I-1

wherein

(a) R¹ is hydrogen, n-alkyl or a substituted or unsubstituted phenyl,where the substitutent of the substituted phenyl is at least one of aC₁₋₃ alkyl, a C₁₋₃ alkoxy, F, Cl, Br, I, nitro, cyano, and a C₁₋₃haloalkyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are independently (i) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 3 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), or CH₂SH and R^(3b) is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, di(lower alkyl)amino-loweralkyl, or aminoacyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂(halo), such as CH₂F, N₃, CH₂CN,CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I,with the provisos that when X is OH, base is cytosine and R⁶ is H, R^(s)cannot be N₃;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂, orO(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂; and

(j) R⁹ is selected from among OH, OCH₃, SH, SCH₃, NH₂, NHCH₃, N(CH₃)₂,OC(O)(C₁₋₂₀ alkyl), which include but are not limited toOC(O)(CH₂)_(s)CH₃, NHC(O)(C₁₋₂₀ alkyl), which include but are notlimited to NHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which includebut is not limited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integerselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, and 19.

A third aspect of the first embodiment is directed to a compoundrepresented by formula I-1

wherein

(a) R¹ is hydrogen, n-alkyl or a substituted or unsubstituted phenyl,where the substitutent of the substituted phenyl is at least one of aCH₃, OCH₃, F, Cl, Br, I, nitro, cyano, and a CH_(3-q)X_(q), where X isF, Cl, Br, or I, and q is 1-3;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl or R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl,di(lower alkyl)amino-lower alkyl, or aminoacyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂(halo), such as CH₂F, N₃, CH₂CN,CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I,with the provisos that when X is OH, base is cytosine and R⁶ is H, R^(s)cannot be N₃;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂, orO(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl′; and

(j) R⁹ is selected from among OH, OCH₃, SH, SCH₃, NH₂, NHCH₃, N(CH₃)₂,OC(O)(C₁₋₂₀ alkyl), which include but are not limited toOC(O)(CH₂)_(s)CH₃, NHC(O)(C₁₋₂₀ alkyl), which include but are notlimited to NHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which includebut is not limited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integerselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, and 19.

A fourth aspect of the first embodiment is directed to a compoundrepresented by formula I-2

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substitutedor unsubstituted phenyl, where the substitutent of the substitutedphenyl is at least one of a CH₃, OCH₃, F, Cl, Br, I, nitro, cyano, and aCH₃-qX_(q), where X is F, Cl, Br, or I, and q is 1-3;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl or R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, N₃, CH₂CN, CH₂N3, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I, with theprovisos that when X is OH, base is cytosine and R⁶ is H, R^(s) cannotbe N₃;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂, orO(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl; and

(j) R⁹ is selected from among OH, OCH₃, SH, SCH₃, NH₂, NHCH₃, N(CH₃)₂,OC(O)(C₁₋₂₀ alkyl), which include but are not limited toOC(O)(CH₂)_(s)CH₃, NHC(O)(C₁₋₂₀ alkyl), which include but are notlimited to NHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃, which include butis not limited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integer selectedfrom 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,and 19.

A fifth aspect of the first embodiment is directed to a compoundrepresented by formula I-2

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl,di(lower alkyl)amino-lower alkyl, or aminoacyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, 1, OC(O)CH₃, OCH₃, orO(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl; and

(j) R⁹ is selected from among OH, OCH₃, SH, SCH₃, NH₂, NHCH₃, N(CH₃)₂,OC(O)(C₁₋₂₀ alkyl), which include but are not limited toOC(O)(CH₂)_(s)CH₃, NHC(O)(C₁₋₂₀ alkyl), which include but are notlimited to NHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which includebut is not limited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integerselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, and 19.

A sixth aspect of the first embodiment is directed to a compoundrepresented by formula I-2

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, OMe, CN, CH₂F, F, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, or N₃, OCH₃, OC(O)CH₃, orO(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂; and

(j) R⁹ is selected from among OH, OCH₃, SH, SCH₃, NH₂, NHCH₃, N(CH₃)₂,OC(O)(C₁₋₂₀ alkyl), which include but are not limited toOC(O)(CH₂)_(s)CH₃, NHC(O)(C₁₋₂₀ alkyl), which include but are notlimited to NHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which includebut is not limited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integerselected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, and 19.

A seventh aspect of the first embodiment is directed to a compoundrepresented by formula I-2

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, or N₃;

(h) Y is OH, OCH₃, OC(O)CH₃, or O(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂; and

(j) R⁹ is selected from among OH, OCH₃, NH₂, NHCH₃, N(CH₃)₂, OC(O)(C₁₋₂₀alkyl), which include but are not limited to OC(O)(CH₂)_(s)CH₃,NHC(O)(C₁₋₂₀ alkyl), which include but are not limited toNHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which include but is notlimited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integer selected fromamong 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,and 19.

An eighth aspect of the first embodiment is directed to a compoundrepresented by formula I-2

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, or N₃;

(h) Y is OH, OCH₃, OC(O)CH₃, or O(aminoacyl);

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂;

(j) R⁹ is selected from among OH, OCH₃, NH₂, NHCH₃, N(CH₃)₂, OC(O)(C₁₋₂₀alkyl), which include but are not limited to OC(O)(CH₂)_(s)CH₃,NHC(O)(C₁₋₂₀ alkyl), which include but are not limited toNHC(O)(CH₂)_(s)CH₃, and N(C(O)(CH₂)_(s)CH₃)₂, which include but is notlimited to N(C(O)(CH₂)_(s)CH₃)₂, where s is an integer selected fromamong 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,and 19.

A second embodiment of the invention is directed to a compoundrepresented by formula I in which the base is a structure represented byformula b above, wherein R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, X, Y, R⁷,and R⁸ are defined in the Summary of the Invention section above.

A first aspect of the second embodiment is directed to a compoundrepresented by formula I-3

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl: (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀oacyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, or N(C₁₋₁₈ acyl)₂, whereinalkyl, alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN,one to three halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄alkyl), C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl),S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl),SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl),SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl),NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, or N(C₁₋₄ acyl)₂;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, loweralkenyl of C₂-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, wherein R′ is aC₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆ alkynyl.

The second aspect of the second embodiment is directed to a compoundrepresented by formula I-3

wherein

(a) R¹ is hydrogen, n-alkyl or aryl, which includes, but is not limitedto, phenyl or naphthyl, where phenyl or naphthyl are optionallysubstituted with at least one of C₁₋₆ alkyl, C₁₋₆ alkoxy, F, Cl, Br, I,nitro, cyano, C₁₋₆ haloalkyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are independently (i) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 3 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), or CH₂SH and R^(3b) is H;

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, CN, CH₃, vinyl, OCH₃, OCH₂CH₃, CH₂OH, CH₂(halo), such asCH₂F, N₃, CH₂CN, CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, includingF, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, vinyl, N₃, CN, Cl, Br, F, I, O(C₁₋₆ acyl),O(C₁₋₄ alkyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl),NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl,alkenyl and vinyl are optionally substituted by N₃, CN, one to threehalogen (Cl, Br, F, I), NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl),OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl,O(aminoacyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl),SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl),SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl),NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂,N(C₁₋₄ acyl)₂;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, lower alkyl, halogenated (F, Cl, Br, I) lower alkyl, loweralkenyl of C₂-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, wherein R′ is aC₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆ alkynyl.

The third aspect of the second embodiment is directed to a compoundrepresented by formula I-3

wherein

(a) R¹ is hydrogen, n-alkyl or a substituted or unsubstituted phenyl,where the substitutent of the substituted phenyl is at least one of aC₁₋₃ alkyl, a C₁₋₃ alkoxy, F, Cl, Br, I, nitro, cyano, and a C₁₋₃haloalkyl;

(b) R² is hydrogen, CH₃, R^(3a) or R^(3b) and R² together are (CH₂)₃ soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), and R^(3b) areas defined herein;

(c) R^(3a) and R^(3b) are independently (i) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 3 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂(halo), such as CH₂F, N₃, CH₂CN,CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, halogen, NH₂, or N₃

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂.

The fourth aspect of the second embodiment is directed to a compoundrepresented by formula I-3

wherein

(a) R¹ is hydrogen, n-alkyl or a substituted or unsubstituted phenyl,where the substitutent of the substituted phenyl is at least one of aCH₃, OCH₃, F, Cl, Br, I, nitro, cyano, and a CH_(3-q)X_(q), where X isF, Cl, Br, or I, and q is 1-3;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl or R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂(halo), such as CH₂F, N₃, CH₂CN,CH₂N3, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl.

The fifth aspect of the second embodiment is directed to a compoundrepresented by formula I-4

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substitutedor unsubstituted phenyl, where the substitutent of the substitutedphenyl is at least one of a CH₃, OCH₃, F, Cl, Br, I, nitro, cyano, and aCH_(3-q)X_(q), where X is F, Cl, Br, or I, and q is 1-3;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl or R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, N₃, CH₂CN, CH₂N3, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl,

The sixth aspect of the second embodiment is directed to a compoundrepresented by formula I-4

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl,Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R⁷ and R⁸ are independently H, F, Cl, Br, I, OH, OCH₃, SH, SCH₃,NH₂, NHCH₃, N(CH₃)₂, CH₃, CH_(3-q)X_(q), where X is F, Cl, Br, or I andq is 1 to 3, vinyl, CO₂H, CO₂CH₃, CONH₂, CONHCH₃, or CON(CH₃)₂, whereinR′ is a C₁₋₂₀ alkyl; a C₁₋₂₀ cycloalkyl; a C₂-C₆ alkenyl, a C₂-C₆alkynyl.

The seventh aspect of the second embodiment is directed to a compoundrepresented by formula I-4

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, OMe, CN, CH₂F, F, Cl, Br, or I;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH3, or OC(O)CH₃;

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂;

The eighth aspect of the second embodiment is directed to a compoundrepresented by formula I-4

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(i)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂.

The ninth aspect of the second embodiment is directed to a compoundrepresented by formula I-4

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, or N₃;

(h) Y is OH, OCH₃, or OC(O)CH₃;

(i) R⁷ and R⁸ are independently H, F, Br, SCH₃, CH₃, CH_(3-q)X_(q),where X is F, Cl, Br, or I and q is 1 to 3, vinyl, CO₂CH₃, CONH₂,CONHCH₃, or CON(CH₃)₂.

A third embodiment of the invention is directed to a compoundrepresented by formula I in which the base is a structure represented byformula c above, wherein R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, X, Y, Z,R¹⁰, R¹¹, and R¹² are defined in the Summary of the Invention sectionabove; with the proviso that R¹¹ is not H.

A first aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is from H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R¹⁰ and R¹¹ are independently H, F, Cl, Br, I, OH, OR′, SH, SR′,NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) loweralkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆ such as C≡CH, halogenated (F,Cl, Br, I) lower alkynyl of C₂-C₆, lower alkoxy of C₁₋C₆, halogenated(F, Cl, Br, I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the proviso that when R¹⁰ is OHand R¹¹ is not NH₂;

wherein R′ is an optionally substituted alkyl, which includes, but isnot limited to, an optionally substituted C₁₋₂₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted lower alkyl; anoptionally substituted cycloalkyl; an optionally substituted alkynyl ofC₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, or optionallysubstituted acyl, which includes but is not limited to C(O)alkyl,C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂,NHR′, NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) loweralkyl of C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl; Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H,or CH═CHCO₂R′.

A second aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl, lower haloalkyl, ordi(lower alkyl)amino-lower alkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵ cannotbe H.

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A third aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I; with the proviso that X is OH,R⁶ is CH₃ or CH₂F, R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A fourth aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A fifth aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A sixth aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵ cannotbe H.

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A seventh aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, tBu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I; with the proviso that X is OH,R⁶ is CH₃ or CH₂F, R^(S) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

An eighth aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A ninth aspect of the third embodiment is directed to a compoundrepresented by formula I-5

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, or N-methyl-pyrrolidin-4-yl, lower haloalkyl,or di(lower alkyl)amino-lower alkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A tenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R′ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂Cl₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R)₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

An eleventh aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl,Br, or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R^(s)cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A twelfth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I, with the provisos that when X isOH, R⁶ is CH₃ or CH₂F, R^(s) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, N₁—I₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is a H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂, NO₂,lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A thirteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R′ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A fourteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R′ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂,CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, with the provisothat when R¹⁰ is OH and R¹¹ is not NH₂;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR¹²,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A fifteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR³, aryl and aryl C₁₋₃ alkyl, saidaryl groups optionally substituted with a group selected from hydroxyl,C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii) R^(3a) andR^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) together are(CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen and R^(3b)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a) and R²together are (CH₂)_(n) so as to form a cyclic ring that includes theadjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to 3, fis 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogen orC₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

An sixteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl,Br, or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R^(s)cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A seventeenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I, with the provisos that when X isOH, R⁶ is CH₃ or CH₂F, R^(s) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

An eighteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′,CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A nineteenth aspect of the third embodiment is directed to a compoundrepresented by formula I-6

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F,R^(S) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is NH₂ and R¹¹ are independently H, F, Br, I, OH, OR′, NH₂,NHR′, NR′₂, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′;

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A fourth embodiment of the invention is directed to a compoundrepresented by formula I in which the base is a structure represented byformula c above, where R¹¹ is H and R², R^(3a), R^(3b), R⁴, R⁵, R⁶, X,and Y are defined in the Summary of the Invention section above.

A first aspect of the fourth embodiment is directed to a compoundrepresented by formula I-7

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R)₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁶cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C1-18 acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R¹⁰ is H, F, Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, loweralkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, loweralkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆,lower alkynyl of C₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′,

wherein R′ is an optionally substituted alkyl, which includes, but isnot limited to, an optionally substituted C₁₋₂₀ alkyl, an optionallysubstituted C₁₋₁₀ alkyl, an optionally substituted lower alkyl; anoptionally substituted cycloalkyl; an optionally substituted alkynyl ofC₂-C₆, an optionally substituted lower alkenyl of C₂-C₆, or optionallysubstituted acyl, which includes but is not limited to C(O)alkyl,C(O)(C₁₋₂₀ alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is H, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′,NR′₂, NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkylof C₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkenyl of C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I)lower alkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br,I) lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H,or CH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.

A second aspect of the fourth embodiment is directed to a compoundrepresented by formula I-7

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵ cannotbe H.

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, halogen, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂, NO₂,lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A third aspect of the third embodiment is directed to a compoundrepresented by formula I-7

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₂F, F, Cl, Br, or I; with the proviso that X isOH, R⁶ is CH₃ or CH₂F, R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂, NO₂,lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A fourth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-7

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F,R^(s) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ and R¹¹ H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂,CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A fifth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-7

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂, NO₂,lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′.

A sixth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-8

wherein

(a) R′ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R⁵ cannotbe N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂, NO₂,lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.

A seventh aspect of the fourth embodiment is directed to a compoundrepresented by formula I-8

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(i)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl,Br, or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, halogen, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

An eighth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-8

wherein

(a) R′ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I, with the provisos that when X isOH, R⁶ is CH₃ or CH₂F, R^(s) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A tenth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-8

wherein

(a) R′ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A ninth aspect of the fourth embodiment is directed to a compoundrepresented by formula I-8

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

(i) R¹⁰ is H, F, Br, I, OH, OR′, NH₂, NHR′, NR′₂, CO₂R′, CONH₂, CONHR′,CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′,

wherein R′ is a lower alkyl, a lower cycloalkyl, or C(O)(lower alkyl) oralternatively, in the instance of NR′₂, each R′ comprise at least one Catom that are joined to form a heterocycle comprising at least twocarbon atoms; and

(j) Z is N or CR¹²; and

R¹² is an H, halogen (including F, Cl, Br, I), OR′, NH₂, NHR′, NR′₂,NO₂, lower alkyl of C₁-C₆, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that R¹² is not a: (i) —C≡C—H, (ii) —C═CH₂,or (iii) —NO₂.

A fifth embodiment of the invention is directed to a compoundrepresented by formula I in which the base is a structure represented byformula d above, wherein R¹, R², R^(3a), R^(3b), R⁴, R⁵, R⁶, X, and Yare defined in the Summary of the Invention section above.

The first aspect of the fifth embodiment is directed to a compoundrepresented by formula I-9

wherein

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(Rr)₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂);

(b) R² is hydrogen or CH₃;

(c) R^(3a) and R^(3b) are (i) independently selected from hydrogen,C₁₋₁₀ alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl,—CH₂SH, —(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂);

(d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyl optionally substituted witha lower alkyl, alkoxy or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, di(loweralkyl)amino-lower alkyl, aryl, such as phenyl, heteroaryl, such as,pyridinyl, substituted aryl, or substituted heteroaryl;

(e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl loweralkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxylmethyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne(optionally substituted), or halogen, including F, Cl, Br, or I, withthe provisos that when X is OH, base is cytosine and R⁶ is H, R^(s)cannot be N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base,R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OMe, halogen, NH₂, or N₃;

(h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN,Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl),S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄alkynyl), SO₂(C₂₋₄ alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl),OS(O)₂(C₂₋₄ alkenyl), NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄alkynyl), NH(C₁₋₄ acyl), N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl,alkynyl, alkenyl and vinyl are optionally substituted by N₃, CN, one tothree halogen (Cl, Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl),C(O)O(C₂₋₄ alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl),O(C₂₋₄ alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄alkenyl), SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄alkenyl), SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄alkenyl), OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl),NH₂, NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂.

A second aspect of the fifth embodiment is directed to a compoundrepresented by formula I-9

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R^(s)cannot be H.

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, halogen, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃;

A third aspect of the fifth embodiment is directed to a compoundrepresented by formula I-9

wherein

(a) R′ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, CN, CH₂F, F, Cl, Br, or I; with the proviso that X isOH, R⁶ is CH₃ or CH₂F, R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂N3, OCH₃, or OC(O)CH₃;

A fourth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-9

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(t)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R^(s) is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F,R^(s) cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

A fifth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-9

wherein

(a) R′ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

A sixth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-10

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, or a substitutedor unsubstituted phenyl, where the substitutent of the substitutedphenyl is at least one of a CH₃, OCH₃, F, Cl, Br, I, nitro, cyano, and aCH_(3-q)X_(q), where X is F, Cl, Br, or I, and q is 1-3;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl or R^(3a) is CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, N₃, CH₂CN, CH₂N3, CH₂NH₂,CH₂NHCH₃, CH₂N(CH₃)₂, halogen, including F, Cl, Br, or I, with theprovisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃;

(h) Y is OH, H, CH₃, vinyl, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃, NH₂,NHCH₃, NH(vinyl), NH(acetyl), NH(C(O)CH₃), N(CH₃)₂, N(C(O)CH₃)₂;

A seventh aspect of the fifth embodiment is directed to a compoundrepresented by formula I-10

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₃, OCH₃, CH₂OH, CH₂F, halogen, including F, Cl, Br,or I, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵ cannotbe H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN;

(g) X is H, OH, F, OCH₃, Cl, Br, I, NH₂, or N₃; and

(h) Y is OH, H, CH₃, vinyl, NH₂, N₃, CN, Cl, Br, F, I, OC(O)CH₃, OCH₃.

An eighth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-10

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen or CH₃;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, CN, CH₂F, F, Cl, Br, or I, with the provisos that when X isOH, R⁶ is CH₃ or CH₂F, R⁵ cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, F, OCH₃, F, Cl, Br, I, NH₂ or N₃;

(h) Y is H, OH, CH₃, F, Cl, Br, I, NH₂ or N₃, OCH₃, or OC(O)CH₃;

A ninth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-10

wherein

(a) R¹ is hydrogen, methyl, ethyl, n-propyl, i-propyl, phenyl, p-tolyl,p-bromo-phenyl, p-chloro-phenyl, p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃;

A tenth aspect of the fifth embodiment is directed to a compoundrepresented by formula I-10

wherein

(a) R¹ is hydrogen, methyl, phenyl, p-bromo-phenyl, p-chloro-phenyl,p-fluorophenyl;

(b) R² is hydrogen;

(c) R^(3a) is H and R^(3b) is H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, or lower cycloalkyl;

(d) R⁴ is hydrogen, CH₃, Et, ^(i)Pr, ^(n)Pr, ^(n)Bu, 2-butyl, ^(t)Bu,benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,N-methyl-aziridin-2-yl, N-methyl-azetidin-3-yl,N-methyl-pyrrolidin-3-yl, N-methyl-pyrrolidin-4-yl,N-methyl-piperidin-4-yl, lower haloalkyl, or di(lower alkyl)amino-loweralkyl;

(e) R⁵ is H, with the provisos that when X is OH, R⁶ is CH₃ or CH₂F, R⁵cannot be H;

(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, or F;

(g) X is H, OH, OCH₃, F, NH₂ or N₃;

(h) Y is OH, NH₂, OCH₃, or OC(O)CH₃.

The following tables contain numeric identifiers associated with varioussubstituent designators that should be viewed in light of theaccompanying structure. These structures are contemplated species of thevarious aspects of the disclosed embodiments and are not intended to belimiting on full breadth of the contemplated compound represented by thestructure of formula I. However, it is contemplated that any one of theexemplified nucleoside bases can be used in combination with any one ofcontemplated species that specify a particular combination of R¹, R²,R^(3a), R^(3b), R⁴, R⁵, R⁶, X, and Y. In each of the presented tables,the phosphoramidate substituent containing the substituents R^(3a) andR^(3b) are depicted without reference to stereochemical structure (cf.structures I-1, I-3, I-5, I-7, and I-9 above). It is contemplated thatthe compounds recited below embody compounds in which R^(3a) projectstoward the viewer while R^(3b) projects away from the viewer (cf.structures I-2, I-4, I-6, I-8, and I-10). Moreover, it is contemplatedthat the compounds recited below also embody compounds in which R^(3a)projects away from the viewer while R^(3b) projects towards the viewer.Not meant to be limiting, however, it is contemplated that preferredcompounds are those in which R^(3a) projects towards the viewer andR^(3b) projects away from the viewer such that the natural L-amino acid(S)-configuration is presented. Additionally, the inventors recognizethat the phosphorus atom of the phosphoramidate moiety is another sourceof chirality. Although the structures below do not specifically depictchirality at phosphorus, the inventors recognize that stereochemicalconfigurations are possible such that in a staggered (or zig-zag) linestructure the oxo-substitutent projects towards the viewer while the OR¹substitutent projects away from the viewer, and vice versa, i.e., wherethe Cahn-Ingold-Prelog stereochemical designation of phosphorous iseither R or S. Therefore, the structures below include all possiblestereochemical configurations possible for phosphorus.

Lengthy table referenced here US20140288020A1-20140925-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00002 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00003 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00004 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00005 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00006 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00007 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00008 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00009 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00010 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00011 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00012 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00013 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00014 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00015 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00016 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00017 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00018 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00019 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00020 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00021 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00022 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00023 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00024 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00025 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00026 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00027 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00028 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00029 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00030 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20140288020A1-20140925-T00031 Pleaserefer to the end of the specification for access instructions.

Dosage, Administration, and Use

A sixth embodiment of the present invention is directed to a compositionfor the treatment of any of the viral agents disclosed herein saidcomposition comprising a pharmaceutically acceptable medium selectedfrom among an excipient, carrier, diluent, and equivalent medium and acompound, that is intended to include its salts (acid or basic additionsalts), hydrates, solvates, and crystalline forms can be obtained,represented by formula I.

It is contemplated that the formulation of the sixth embodiment cancontain any of the compounds contemplated in any of the aspects of thefirst, second, third, fourth, and fifth embodiments or thosespecifically recited in the tables above or exemplified herein, eitheralone or in combination with another compound of the present invention.

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, hard andsoft gelatin capsules, solutions, emulsions, syrups, or suspensions.Compounds of the present invention are efficacious when administered bysuppository administration, among other routes of administration. Themost convenient manner of administration is generally oral using aconvenient daily dosing regimen which can be adjusted according to theseverity of the disease and the patient's response to the antiviralmedication.

A compound or compounds of the present invention, as well as theirpharmaceutically acceptable salts, together with one or moreconventional excipients, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds and the unit dosage forms may contain any suitableeffective amount of the active ingredient commensurate with the intendeddaily dosage range to be employed. The pharmaceutical compositions maybe employed as solids, such as tablets or filled capsules, semisolids,powders, sustained release formulations, or liquids such as suspensions,emulsions, or filled capsules for oral use; or in the form ofsuppositories for rectal or vaginal administration. A typicalpreparation will contain from about 5% to about 95% active compound orcompounds (w/w). The term “preparation” or “dosage form” is intended toinclude both solid and liquid formulations of the active compound andone skilled in the art will appreciate that an active ingredient canexist in different preparations depending on the desired dose andpharmacokinetic parameters.

The term “excipient” as used herein refers to a compound that is used toprepare a pharmaceutical composition, and is generally safe, non-toxicand neither biologically nor otherwise undesirable, and includesexcipients that are acceptable for veterinary use as well as humanpharmaceutical use. The compounds of this invention can be administeredalone but will generally be administered in admixture with one or moresuitable pharmaceutical excipients, diluents or carriers selected withregard to the intended route of administration and standardpharmaceutical practice.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound as used herein means asalt that is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as glycolic acid, pyruvicacid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylicacid, muconic acid, and the like or (2) basic addition salts formed withthe conjugate bases of any of the inorganic acids listed above, whereinthe conjugate bases comprise a cationic component selected from amongNa⁺, K⁺, Mg²⁺, Ca²⁺, and NH_(g)R′″_(4-g) ⁺, in which R′″ is a C₁₋₃ alkyland g is a number selected from among 0, 1, 2, 3, or 4. It should beunderstood that all references to pharmaceutically acceptable saltsinclude solvent addition forms (solvates) or crystal forms (polymorphs)as defined herein, of the same acid addition salt.

Solid form preparations include powders, tablets, pills, capsules,suppositories, and dispersible granules. A solid carrier may be one ormore substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs and aqueoussuspensions. These include solid form preparations which are intended tobe converted to liquid form preparations shortly before use. Emulsionsmay be prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents such as lecithin, sorbitanmonooleate, or acacia. Aqueous suspensions can be prepared by dispersingthe finely divided active component in water with viscous material, suchas natural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well known suspending agents.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

Suitable formulations along with pharmaceutical carriers, diluents andexpedients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E, W. Martin, Mack Publishing Company, 19thedition, Easton, Pa., which is hereby incorporated by reference. Thecompounds of the present invention can also be encapsulated inliposomes, such as those disclosed in U.S. Pat. Nos. 6,180,134,5,192,549, 5,376,380, 6,060,080, 6,132,763, each of which isincorporated by reference. A skilled formulation scientist may modifythe formulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (e.g., salt formulation), which are well within theordinary skill in the art. It is also well within the ordinary skill ofthe art to modify the route of administration and dosage regimen of aparticular compound in order to manage the pharmacokinetics of thepresent compounds for maximum beneficial effect in patients.

A seventh embodiment of the present invention is directed to a use ofthe compound represented by formula I in the manufacture of a medicamentfor the treatment of any condition the result of an infection by any oneof the following viral agents: hepatitis C virus, West Nile virus,yellow fever virus, dengue virus, rhinovirus, polio virus, hepatitis Avirus, bovine viral diarrhea virus and Japanese encephalitis virus.

The terra “medicament” means a substance used in a method of treatmentand/or prophylaxis of a subject in need thereof, wherein the substanceincludes, but is not limited to, a composition, a formulation, a dosageform, and the like, comprising the compound of formula I. It iscontemplated that the compound of the use of the compound represented byformula I in the manufacture of a medicament for the treatment of any ofthe antiviral conditions disclosed herein of the seventh embodiment canbe any of the compounds contemplated in any of the aspects of the first,second, third, fourth, fifth embodiments or those specifically recitedin the tables above or exemplified herein, either alone or incombination with another compound of the present invention. A medicamentincludes, but is not limited to, any one of the compositionscontemplated by the sixth embodiment of the present invention.

A eighth embodiment of the present invention is directed to a method oftreatment and/or prophylaxis in a subject in need thereof said methodcomprises administering a therapeutically effective amount of thecompound represented by formula I to the subject.

A first aspect of the eighth embodiment is directed to a method oftreatment and/or prophylaxis in a subject in need thereof said methodcomprises administering a therapeutically effective of at least two ormore different compounds falling within the scope of the compoundrepresented by formula I to the subject.

A second aspect of the eighth embodiment is directed to a method oftreatment and/or prophylaxis in a subject in need thereof said methodcomprises alternatively or concurrently administering a therapeuticallyeffective of at least two compounds falling within the scope of thecompound represented by formula I to the subject.

It is intended that a subject in need thereof is one that has anycondition the result of an infection by any of the viral agentsdisclosed herein, which includes, but is not limited to, hepatitis Cvirus, West Nile virus, yellow fever virus, dengue virus, rhinovirus,polio virus, hepatitis A virus, bovine viral diarrhea virus or Japaneseencephalitis virus, flaviviridae viruses or pestiviruses orhepaciviruses or a viral agent causing symptoms equivalent or comparableto any of the above-listed viruses.

The term “subject” means a mammal, which includes, but is not limitedto, cattle, pigs, sheep, chicken, turkey, buffalo, llama, ostrich, dogs,cats, and humans, preferably the subject is a human. It is contemplatedthat in the method of treating a subject thereof of the sixth embodimentcan be any of the compounds contemplated in any of the aspects of thefirst, second, and third embodiments or those specifically recited inthe tables above, either alone or in combination with another compoundof the present invention.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.1 and about 10 g,including all values in between, such as 0.25, 0.5, 0.75, 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, and 9.5, per dayshould be appropriate in monotherapy and/or in combination therapy. Apreferred daily dosage is between about 0.5 and about 7.5 g per day,more preferred 1.5 and about 6.0 g per day. Generally, treatment isinitiated with a large initial “loading dose” to rapidly reduce oreliminate the virus following by a decreasing the dose to a levelsufficient to prevent resurgence of the infection. One of ordinary skillin treating diseases described herein will be able, without undueexperimentation and in reliance on personal knowledge, experience andthe disclosures of this application, to ascertain a therapeuticallyeffective amount of the compounds of the present invention for a givendisease and patient.

Therapeutic efficacy can be ascertained from tests of liver functionincluding, but not limited to protein levels such as serum proteins(e.g., albumin, clotting factors, alkaline phosphatase,aminotransferases (e.g., alanine transaminase, aspartate transaminase),5′-nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis ofbilirubin, synthesis of cholesterol, and synthesis of bile acids; aliver metabolic function, including, but not limited to, carbohydratemetabolism, amino acid and ammonia metabolism. Alternatively thetherapeutic effectiveness may be monitored by measuring HCV-RNA. Theresults of these tests will allow the dose to be optimized.

A third aspect of the eighth embodiment, is directed to a method oftreatment and/or prophylaxis in a subject in need thereof said methodcomprises administering to the subject a therapeutically effective of acompound represented by formula I and a therapeutically effective amountof another antiviral agent; wherein the administration is concurrent oralternative. It is understood that the time between alternativeadministration can range between 1-24 hours, which includes anysub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours. Examples of “anotherantiviral agents” include, but are not limited to: HCV NS3 proteaseinhibitors (see WO 2008010921, WO 2008010921, EP 1881001, WO 2007015824,WO 2007014925, WO 2007014926, WO 2007014921, WO 2007014920, WO2007014922, US 2005267018, WO 2005095403, WO 2005037214, WO 2004094452,US 2003187018, WO 200364456, WO 2005028502, and WO 2003006490); HCV NS5BInhibitors (see US 2007275947, US20072759300, WO2007095269, WO2007092000, WO 2007076034, WO 200702602, US 2005-98125, WO 2006093801,US 2006166964, WO 2006065590, WO 2006065335, US 2006040927, US2006040890, WO 2006020082, WO 2006012078, WO 2005123087, US 2005154056,US 2004229840, WO 2004065367, WO 2004003138, WO 2004002977, WO2004002944, WO 2004002940, WO 2004000858. WO 2003105770, WO 2003010141,WO 2002057425, WO 2002057287, WO 2005021568, WO 2004041201, US20060293306, US 20060194749, US 20060241064, U.S. Pat. No. 6,784,166, WO2007088148, WO 2007039142, WO 2005103045, WO 20070391.45, WO 2004096210,and WO 2003037895); HCV NS4 Inhibitors (see WO 2007070556 and WO2005067900); HCV NS5a Inhibitors (see US 2006276511, WO 2006120252, WO2006120251, WO 2006100310, WO 2006035061); Toll-like receptor agonists(see WO) 2007093901); and other inhibitors (see WO 2004035571, WO2004014852, WO 2004014313, WO 2004009020, WO 2003101993, WO 2000006529),

A fourth aspect of the eighth embodiment, is directed to a method oftreatment in a subject in need thereof said method comprisesalternatively or concurrently administering a therapeutically effectiveof a compound represented by formula I and another antiviral agent tothe subject. It is understood that the time between alternativeadministration can range between 1-24 hours, which includes anysub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.

A fifth aspect of the eighth embodiment, is directed to a method oftreatment and/or prophylaxis in a subject in need thereof said methodcomprises administering to the subject a therapeutically effective of atleast one compound represented by formula I and a therapeuticallyeffective amount of another antiviral agent; wherein the administrationis concurrent or alternative. It is understood that the time betweenalternative administration can range between 1-24 hours, which includesany sub-range in between including, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.

A sixth aspect of the eighth embodiment, is directed to a method oftreatment in a subject in need thereof said method comprisesalternatively or concurrently administering a therapeutically effectiveof at least one compound represented by formula I and another antiviralagent to the subject. It is understood that the time between alternativeadministration can range between 1-24 hours, which includes anysub-range in between including, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, and 23 hours.

It is contemplated that the another antiviral agent includes, but is notlimited to interferon-α, interferon-β, pegylated interferon-α,ribavirin, levovirin, viramidine, another nucleoside HCV polymeraseinhibitor, a HCV non-nucleoside polymerase inhibitor, a HCV proteaseinhibitor, a HCV helicase inhibitor or a HCV fusion inhibitor. When theactive compound or its derivative or salt are administered incombination with another antiviral agent the activity may be increasedover the parent compound. When the treatment is combination therapy,such administration may be concurrent or sequential with respect to thatof the nucleoside derivatives. “Concurrent administration” as usedherein thus includes administration of the agents at the same time or atdifferent times. Administration of two or more agents at the same timecan be achieved by a single formulation containing two or more activeingredients or by substantially simultaneous administration of two ormore dosage forms with a single active agent.

It will be understood that references herein to treatment extend toprophylaxis as well as to the treatment of existing conditions.Furthermore, the term “treatment” of a HCV infection, as used herein,also includes treatment or prophylaxis of a disease or a conditionassociated with or mediated by HCV infection, or the clinical symptomsthereof.

Process for Preparation

An ninth embodiment of the present invention is directed to a processfor preparing the compound of formula I, which comprises reacting asuitably substituted phosphochloridate compound 4 with a nucleosideanalog 5

wherein the substituents R¹, R², R^(3a), R^(3b), R⁴, R⁵, X, Y, R⁶, andbase have their meanings as disclosed in the Detailed Description of theinvention and X′ is a leaving group, such as Cl, Br, I, tosylate,mesylate, trifluoroacetate, trifluorosulfonate, pentafluorophenoxide,p-NO₂-phenoxide, or other commonly used leaving groups as disclosed inAdvanced Organic Chemistry by March, Fourth Edition. Leaving groups andmethods that can be used to effect the formation of a phosphoramidatenucleoside conjugate are found in US 20060142238 and WO 2007095269.Preferably, the leaving group is Cl.

This reaction is performed in an anhydrous aprotic solvent suchtetrahydrofuran, dioxane, or both tetrahydrofuran and dioxane, or anyfunctional equivalent thereof, with tetrahydrofuran being the preferredsolvent. The reaction is typically initiated at a temperature range from−78° C. to 40° C. with the preferred reaction temperature being between0° C. and room temperature. The nucleoside is first stirred with a base(5 to 12 equivalents) such as N-methylimidazole, collidine, pyridine,2,6-lutidine, 2,6-Bu-pyridine, etc. a tertiary amine base, such astriethylamine, diisopropyl ethylamine, etc., or an alkyl Grignardreagent, such as tBuMgCl, tBuMgBr, MeMgCl, MeMgBr, etc. Thephosphorochloridate (3-10 equivalents) is dissolved in the reactionsolvent and added to the mixture of the nucleoside and base. Thereaction is then allowed to stir over a period of time at a temperaturebetween room temperature and 40° C. for a period of 30 min to 24 hr.with the preferred reaction temperature being room temperature and timebeing 24 hr. The solvent is removed from the reaction mixture and theproduct is purified by chromatography on silica gel.

A tenth embodiment of the present invention is directed to a productobtained by a process which comprises reacting a suitably substitutedphosphochloridate compound 4 with a nucleoside analog 5

wherein the substituents R¹, R², R^(3a), R^(3b), R⁴, R⁵, X, Y, R⁶, X′,and base have their meanings as disclosed in the Detailed Description ofthe Invention.

This reaction can be performed in an anhydrous aprotic solvent or othersuitable solvent, such as tetrahydrofuran, dioxane, or a mixture oftetrahydrofuran and dioxane, with tetrahydrofuran being the preferredsolvent. The reaction is typically initiated at a temperature range from−78° C. to 40° C. with the preferred reaction temperature being between0° C. and room temperature. The nucleoside is first stirred with a base(5 to 12 equivalents) such as N-methylimidazole, a tertiary amine baseor tButyl Magnesium Chloride. A phosphorochloridate (3-10 equivalents(or suitable “phosphoro-(leaving group)-date”)) is dissolved in thereaction solvent and added to the mixture of the nucleoside and base.The reaction is then allowed to stir over a period of time at atemperature between room temperature and 40° C. for a period of 30 minto 24 hr. with the preferred reaction temperature being room temperatureand time being 24 hr. The solvent is removed from the reaction mixtureand the product is purified by chromatography on silica gel.

Compounds and Preparation

Phosphoramidate compounds of the present invention can be prepared bycondensation of a nucleoside analog 5 with a suitably substitutedphosphochloridate compound 4 (Scheme 1). The nucleoside analog is madeby conventional procedures disclosed in any one of U.S. PublishedApplication Nos. 2005/0009737, 2006/0199783, 2006/0122146, and2007/0197463, each of which is incorporated by reference in itsentirety.

Disclosed 1H-NMR values were recorded on a Varian AS-400 instrument.Mass spectral data were obtain using either a Micromass-Quattromicro APIor a Waters Acquity.

Thus, by way of example only, a suitably substituted phenol can bereacted with phosphorus oxychloride (1) to afford an aryloxyphosphorodichloridate 2 (see Example 1) which is subsequently treatedwith a acid addition salt of an α-amino acid ester in the presence ofTEA to afford an aryloxy phosphorochloridate 4. This arylalkoxy-aminoacid phosphoramidate is reacted with the nucleoside analog to providethe product I (for procedure see, e.g., C. McGuigan et al. AntiviralRes. 1992 17:311-321; D. Curley et al. Antiviral Res. 1990 14:345-356;McGuigan et al. Antiviral Chem. Chemother 1990 1(2):107-113).

The preparation of nucleoside phosphoramidates requires reacting anappropriately substituted phosphochloridate with a nucleoside containinga free 5′-hydroxyl moiety. In cases where only one hydroxyl group ispresent, preparation of the phosphoramidate usually proceeds smoothlywhen the phosphochloridate is reacted with the desired nucleoside. Incases where the nucleoside contains more than one free hydroxyl group,preparation of the appropriately protected nucleoside might be required.Silyl, acetonide or other alcohol protecting groups known in the artmight be warranted for protection of the sugar moiety. For protection ofthe nucleoside base, protecting a free amino group may require amidineprotection strategy,

Condensation of the phosphochloridate can be carried out on theunprotected nucleoside. Since the 5′-OH group of a nucleoside is muchless hindered than the 3′-OH group, selective phosphoramidation ispossible under carefully controlled conditions. After condensation toform a protected phosphoramidate nucleoside, deprotection to obtain thefree phosphoramidate nucleoside can be carried out using standardprotocols for nucleic acid chemistry. In many cases, the desired productis readily separated from the starting material using columnchromatography on silica gel. The synthetic scheme is summarized inScheme 1.

A further understanding other understanding of the disclosed embodimentswill be appreciated by consideration of the following examples, whichare only meant to be illustrative, and not limit the disclosedinvention.

Example I General Procedure for Preparation of Phosphorodichloridates

A solution of the appropriate phenol R¹—OH (1 eq) and triethylamine (1eq.) in anhydrous ether was added dropwise to a stirred solution ofphosphoryl trichloride 1 (1 eq) at 0° C. over a period of 3 hours undernitrogen. Then the temperature was warmed to room temperature, and thereaction was stirred overnight. The triethylamine salt was quicklyremoved with suction filtration and the filtrate concentrated in vacuoto dryness to afford 2 as an oil which was used without furtherpurification.

Example 2 General Procedure for Preparation of Phosphorochloridates

A solution of triethylamine (2 eq) in anhydrous dichloromethane wasadded dropwise to a solution of aryloxy-phosphodichloridate 2 (1 eq) andthe appropriate amino ester 3 (1 eq) in anhydrous dichloromethane withvigorous stirring at −78° C. over a period of 30 to 120 minutes. Thenthe reaction temperature was allowed to warm to room temperature andstirred over night. Solvent was removed. The residue was washed withethyl ether and filtered, the filtrate was dried over reduced pressureto give 4.

Example 3 General Procedures for Nucleoside Phosphoramidate Derivatives

A solution of the appropriate phosphorochloridate 4 (6.5 equivalents) inanhydrous tetrahydrofuran (THF) was added to a mixture of nucleoside 5(1 equivalent) and N-methylimidazole (8 equivalents) in anhydrous THFwith vigorous stirring at room temperature and the reaction mixture wasstirred overnight. The solvent was removed in vacuo and the crude waspurified by column chromatography and/or preparative thin layerchromatography to give I.

Example 4 Preparation of 2′-deoxy-2′-fluoro-2′-C-methyluridine

2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J. et al.,J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrouspyridine and concentrated to dryness in vacuo. The resulting syrup wasdissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0°C. with stirring. The brown solution was treated with benzoyl chloride(1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed andstirring continued for 1.5 h whereby thin-layer chromatography (TLC)showed no remaining starting material. The mixture was quenched byaddition of water (0.5 ml) and concentrated to dryness. The residue wasdissolved in 50 mL of dichloromethane (DCM) and washed with saturatedNaHCO₃ aqueous solution and H₂O. The organic phase was dried over NaSO₄and filtered, concentrated to dryness to giveN⁴,3′,5′-tribenzoyl-2′-Deoxy-2-fluoro-2′-C-methylcytidine (2.0 g, Yield:91%).

N⁴,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq)was refluxed in 80% aqueous AcOH overnight. After cooling and standingat room temperature (15° C.), most of the product precipitated and thenwas filtered through a sintered funnel. White precipitate was washedwith water and co-evaporated with toluene to give a white solid. Thefiltrate was concentrated and co-evaporated with toluene to giveadditional product which was washed with water to give a white solid.Combining the two batches of white solid gave 1.50 g of3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-(7-methyluridine (Yield: 91%).

To a solution of 3′,5-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine(1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammoniain MeOH (20 mL).

The reaction mixture was stirred at 0° C. for 30 min, and then warmed toroom temperature slowly. After the reaction mixture was stirred foranother 18 hours, the reaction mixture was evaporated under reducedpressure to give the residue, which was purified by columnchromatography to afford pure compound2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).

Example 5 Preparation of 2′-Deoxy-2′-fluoro-2′-C-methyluridine-5-(phenylmethoxy-alanyl phosphate)

Phenyl methoxyalaninyl phosphorochloridate (1 g, 6.5 eq) dissolved in 3mL of THF was added to a mixture of2′-Deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, 1 eq) andN-methylimidazole (0.3 g, 8 eq) in 3 mL THF with vigorous stirring atroom temperature, then the reaction was stirred overnight. Solvent wasremoved by reduced pressure. The resulting crude product was dissolvedin methanol purified by prep-HPLC on a YMC 25×30×2 mm column using awater/acetonitrile gradient elution mobile phase. The acetonitrile andwater were removed under reduced pressure to give the desired product(50.1 mg, 15.6%). ¹H NMR (DMSO-d₆) δ 1.20-1.27 (m, 6H), 3.58 (d, J=16.0Hz, 3H), 3.75-3.92 (m, 2H), 4.015-4.379 (min, 2H), 5.54 (t, J=10.2 Hz,1H), 5.83-5.91 (m, 1H), 6.00-6.16 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.22(s, 1H), 7.35 (t, J=4.4 Hz, 2H), 7.55 (s, 1H), 11.52 (s, 1H); MS, m/e502 (M+1)⁺.

Example 6 Preparation of 2′-Deoxy-2′-fluoro-2′-C methyluridine5′-(phenyl methoxy-valyl phosphate)

Phenyl methoxy-valyl phosphorochloridate (0.6 g, 3.6 eq) dissolved in 3mL of THF was added to a mixture of2′-Deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, 1 eq) andN-methylimidazole (0.44 g, 9 eq) in 3 mL THF with vigorous stirring atroom temperature, then the reaction was stirred overnight. Solvent wasremoved by reduced pressure. The resulting crude product was dissolvedin methanol purified by prep-HPLC on a YMC 25×30×2 mm column using awater/acetonitrile gradient elution mobile phase. The acetonitrile andwater were removed under reduced pressure to give the desired product(60 mg, 20%). ¹H NMR (DMSO-d₆) δ 0.74-0.847 (m, 6H), 1.20-1.28 (m, 3H),1.89-1.92 (m, 1H), 3.50-3.54 (m, 1H), 3.58 (d, J=10.4 Hz, 3H), 3.72-3.95(m, 1H), 4.03-4.05 (m, 1H), 4.23-4.43 (m, 2H), 5.56 (t, J=16.0 Hz, 1H),5.85-5.92 (m, 1H), 6.01-6.07 (m, 1H), 7.16-7.21 (m, 3H), 7.37 (t, J=8Hz, 2H), 7.55-7.60 (m, 1H), 11.52 (s, 1H); MS, m/e 530 (M+1)⁺.

Example 7 Preparation of 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate)

4-Bromophenyl methoxy-valyl phosphorochloridate (1 g, 3.4 eq) dissolvedin 3 mL of THF was added to a mixture of2′-deoxy-2′-fluoro-2′-C-methyluridine (0.2 g, 1 eq) andN-methylimidazole (0.35 g, 6 eq) in 3 mL THF with vigorous stirring atroom temperature, then the reaction was stirred overnight Solvent wasremoved by reduced pressure. The resulting crude product was dissolvedin methanol purified by prep-HPLC on a YMC 25×30×2 mm column using awater/acetonitrile gradient elution mobile phase. The acetonitrile andwater were removed reduced pressure to give the desired product (120 mg,26%). ¹H NMR (DMSO-d₆) δ 0.72-0.82 (m, 6H), 1.19-1.26 (m, 3H), 1.86-1.92(m, 1H), 3.48-3.50 (m, 1H), 3.56 (d, J=12.0 Hz, 3H), 3.72-3.89 (1H),3.96-4.03 (m, 1H), 4.22-4.37 (min, 2H), 5.54-5.60 (m, 1H), 5.85-5.91(1H), 5.98-6.13 (m, 1H), 7.15 (d, J=8.0 Hz, 2H), 7.49-7.56 (m, 3H),11.53 (s, 1H); MS, m/e 608 (M+1)⁺.

Example 8 Preparation of 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate)

4-Bromophenyl methoxy-alanyl phosphorochloridate (0.6 g, 5 eq) dissolvedin 3 mL of THF was added to a mixture of2′-deoxy-2′-fluoro-2′-C-methyluridine (0.15 g, eq) and N-methylimidazole(0.3 g, 7.8 eq) in 3 mL THF with vigorous stirring at room temperature,then the reaction was stirred overnight. Solvent was removed by reducedpressure. The resulting crude product was dissolved in methanol purifiedby prep-HPLC on a YMC 25×30×2 mm column using a water/acetonitrilegradient elution mobile phase. The acetonitrile and water were removedunder reduced pressure to give the desired product (40 mg, 12%); ¹H NMR(DMSO-d₆) δ 1.20-1.26 (m, 6H), 3.57 (d, J=2.8 Hz, 3H), 3.84 (s, 1H),3.97-4.03 (m, 1H), 4.21-4.25 (m, 1H), 4.33-4.37 (m, 2H), 5.54-5.60 (m,1H), 5.83-5.89 (m, 1H), 5.98-6.19 (m, 1H), 7.16 (t, J=10.2 Hz, 2H),7.52-7.57 (m, 3H), 11.52 (s, 1H); MS, m/e 580 (M+1)⁺.

Example 9 Preparation ofN⁴—(N,N-dimethylformanidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine

2′-Deoxy-2′-fluoro-2′-C-methylcytidine (500 mg, 0.9 mmol) was stirredwith dimethylformamide dimethyl acetal in DMF (10 mL). The resultingmixture was stirred at room temperature overnight. After solvent removalthe crude product was used for next step without further purification.

Example 10 Preparation of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(phenyl methoxy-alanyl phosphate)

Phenyl methoxyalaninyl phosphorochloridate (0.6 g, 6 eq) dissolved in 3mL of THF was added to a mixture ofN⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2-fluoro-2′-methylcytidine (0.15g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF with vigorousstirring at room temperature, then the reaction was stirred overnight.Solvent was removed by reduced pressure. The resulting crude product wasdissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm columnusing a water/acetonitrile gradient elution mobile phase. Theacetonitrile and water were removed under reduced pressure to give thedesired product (62 mg, 20.6%). ¹H NMR (DMSO-d₆) δ 1.16 (d, J=23.2 Hz,3H), 1.22 (d, J=7.2 Hz, 3H), 3.56 (S, 3H), 3.69-3.75 (d, J=25.6 Hz, 1H),3.82-3.86 (m, 1H), 3.96-3.98 (m, 1H), 4.21-4.34 (m, 2H), 5.68 (d, J=7.2Hz, 1H), 5.75-5.77 (m, 1H), 6.07-6.16 (m, 1H), 7.15-7.19 (m, 3H), 7.2(d, J=9.2 Hz, 2H), 7.39 (t, J=7.8 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H); MS,m/e 501 (M+1)⁺.

Example 11 Preparation of 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate)

4-Bromophenyl methoxy-valyl phosphorochloridate (1.0 g 3.4 eq.)dissolved in 3 mL of THF was added to a mixture ofN⁴—(N,N-dimethylformamidinyl)-2-deoxy-2′-fluoro-2′-C-methylcytidine (0.2g, 1 eq.) and N-methylimidazole (0.35 g, 6 eq.) in 3 mL THF withvigorous stirring at room temperature, then the reaction was stirredovernight.

Solvent was removed by reduced pressure. The resulting crude product wasdissolved in methanol purified by prep-HPLC on a YMC 25×30×2 mm columnusing a water/acetonitrile gradient elution mobile phase. Theacetonitrile and water were removed under reduced pressure to give thedesired product as a white solid (59 mg, 13%); ¹H NMR (DMSO-d c) δ0.74-0.83 (m, 6H), 1.12-1.20 (m, 3H), 1.89-1.92 (min, 1H), 3.49-3.51 (m,1H), 3.55 (s, 3H), 3.59-3.68 (m, 1H), 3.72-0.383 (1H), 4.21-4.39 (m,2H), 5.70-5.72 (m, 1H) 5.76-5.83 (m, 1H), 6.04-6.16 (m, 1H), 7.15 (d,J=13.0 Hz, 2H), 7.26 (s, 1H), 7.33 (s, 1H), 7.46-7.55 (m, 1H), 7.56 (d,J=4.4 Hz, 2H); MS, m/e 607 (M+1)⁺.

Example 12 Preparation of 2′-deoxy-2′-fluoro-2′-C-methylcytidine5-(phenyl methoxy-valyl phosphate)

Phenyl methoxy-valyl phosphorochloridate (0.6 g, 6 eq) dissolved in 3 mLof THF was added to a mixture ofN⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine(0.15 g, 1 eq) and N-methylimidazole (0.3 g, 7.8 eq) in 3 mL THF withvigorous stirring at room temperature, then the reaction was stirredovernight. Solvent was removed by reduced pressure The resulting crudeproduct was dissolved in methanol purified by prep-HPLC on a YMC 25×30×2mm column using a water/acetonitrile gradient elution mobile phase. Theacetonitrile and water were removed under reduced pressure to give thedesired product as a white solid (86 mg, 42.9%). ¹H NMR (DMSO-d₆) δ072-0.80 (m, 6H), 1.09-1.18 (m, 3H), 1.87-1.92 (m, 1H), 3.47-3.51 (m,1H), 3.58 (s, 3H), 3.71-3.75 (m, 1H), 3.97 (t, J=11.2 Hz, 1H), 4.22-4.37(m, 2H), 5.70 (d, J=8.0 Hz, 1H), 5.76-5.84 (m, 1H), 6.01-6.15 (m, 1H),7.13-7.18 (m, 3H), 7.27 (s, 2H), 7.34 (d, J=4.0 Hz, 2H), 7.46-7.50 (m,1H); MS, m/e 529 (M+1)⁺.

EXAMPLES

Example numbers 13-54 and 56-66 are prepared using similar proceduresdescribed for examples 5-8. The example number, compound identification,and NMR/MS details are shown below:

Ex. R¹ R² R^(3a) R^(3b) R⁴ NMR/MS 13 Ph H H Me Et 1H NMR (DMSO-d₆) δ1.12-1.16 (m, 3H), 1.20-1.28 (m, 6H), 3.70-3.90 (m, 2H), 4.00-4.08 (m,3H), 4.18-4.45 (m, 2H), 5.52-5.58 (m, 1H), 5.85-5.98 (m, 1H), 6.00-6.20(m, 2H), 7.16-7.23 (m, 3H), 7.37-7.40 (m, 2H), 7.54-7.60 (m, 1H), 11.54(s, 1H); MS, m/e 516.1 (M + 1)+ 14 1-Napth H H Me Bn 1H NMR (DMSO-d₆) δ1.18-1.30 (m, 6H), 3.78-4.10 (m, 3H), 4.38- 4.49 (m, 2H), 4.99-5.11 (m,2H), 5.28-5.40 (m, 1H), 5.85-6.10 (m, 2H), 6.30-6.41 (m, 1H), 7.28-7.32(m, 5H), 7.41-7.60 (m, 5H), 7.73- 7.76 (m, 1H), 7.94-8.11 (m, 1H),8.13-8.15 (m, 1H), 11.50 (s, 1H); MS, m/e 628.4 (M + 1)+ 15 Ph H H H Me1H NMR (DMSO-d₆) δ 1.22 (d, J = 22.4 Hz, 3H), 3.59 (s, 3H), 3.63-3.69(m, 2H), 3.74-3.8 (m, 1H), 4.02 (d, J = 11.2 Hz, 1H), 4.23-4.28 (m, 1H),4.40-4.43 (m, 1H), 5.57-5.60 (m, 1H), 5.89 (d, J = 6.8 Hz, 1H), 6.00-6.06 (m, 2H), 7.15-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.52 (d, J = 8 Hz,1H), 11.52 (s, 1H); MS, m/e 487.97 (M + 1)+ 16 2,4-Cl—Ph H H Me Me 1HNMR (DMSO-d₆) δ 1.22-1.28 (m, 6H), 3.57-3.60 (m, 3H), 3.84- 3.92 (m,2H), 4.00-4.04 (m, 1H), 4.31-4.44 (m, 2H), 5.54-5.61 (m, 1H), 5.85-6.10(m, 2H), 6.32-6.43 (m, 1H), 7.44-7.54 (m, 3H), 7.72- 7.75 (m, 1H), 11.54(s, 1H); MS, m/e 570.2 (M + 1)+ 17 1-Napth H H Me Me 1H NMR (DMSO-d₆) δ1.15-1.27 (m, 6H), 3.51-3.55 (d, 3H), 3.85- 3.96 (m, 2H), 4.00-4.10 (m,1H), 4.30-4.46 (m, 2H), 5.31-5.39 (m, 1H), 5.89-6.05 (m, 2H), 6.22-6.34(m, 1H), 7.44-7.60 (m, 5H), 7.73-7.77 (m, 1H), 7.93-7.96 (m, 1H),8.12-8.14 (m, 1H), 11.50 (s, 1H); MS, m/e 552.1 (M + 1)+ 18 Ph * H * Me1H NMR (DMSO-d₆) δ 1.19 (d, J = 22.8 Hz, 3H), 1.69-1.84 (m, 3H),1.99-2.04 (m, 1H), 3.16-3.21 (m, 2H), 3.58 (s, 3H), 3.68-3.8 (m, 1H),4.00 (m, 1H), 4.01-4.13 (m, 1H), 4.22-4.25 (m, 1H), 4.5 (d, J = 11.2 Hz,1H), 5.54 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), 5.6 (d, J = 19.6 Hz, 1H),7.15-7.2 (m, 3H), 7.34 (t, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H),11.38 (s, 1H); MS, m/e 527.93 (M + 1)+ 19 Ph H H Me n-Bu 1H NMR(DMSO-d₆) δ 0.80-0.90 (m, 3H), 1.20-1.35 (m, 8H), 1.48- 1.55 (m, 2H),3.78-3.88 (m, 2H), 3.95-4.08 (m, 3H), 4.22-4.45 (m, 2H), 5.55-5.57 (t,1H), 5.85-6.18 (m, 3H), 7.14-7.23 (m, 3H), 7.35-7.40 (m, 2H), 7.51-7.60(d, 1H), 11.50 (s, 1H); MS, m/e 544.2 (M + 1)+ 20 Ph H H Me Bn 1H NMR(DMSO-d₆) δ 1.20-1.30 (m, 6H), 3.72-4.05 (m, 3H), 4.23- 4.27 (m, 1H),4.32-4.45 (m, 1H), 5.07-5.10 (t, 2H), 5.52-5.56 (t, 1H), 5.86-6.10 (m,2H), 6.13-6.21 (m, 1H), 7.15-7.21 (m, 3H), 7.29-7.40 (m, 7H), 7.51-7.56(d, 1H), 11.50 (s, 1H); MS, m/e 578.2 (M + 1)+ 21 4-F—Ph H H Me Me 1HNMR (DMSO-d₆) δ 1.28-1.34 (m, 6H), 3.65 (d, J = 4 Hz, 3H), 3.85- 3.96(m, 2H), 4.06-4.12 (m, 1H), 4.30-4.34 (m, 1H), 4.40-4.47 (m, 1H),5.62-5.67 (m, 1H), 5.94-6.01 (m, 1H), 6.09 (d, J = 18.8 Hz, 1H), 6.17-6.26 (m, 1H), 7.27-7.33 (m, 4H), 7.62 (d, J = 7.6 Hz, 1H), 11.61 (s,1H); MS, m/e 519.94 (M + 1)+ 22 4-Cl—Ph H H Me Me 1H NMR (DMSO-d₆) δ1.22-1.28 (m, 6H), 3.58 (d, 2H), 3.70- 3.95 (m, 2H), 3.95-4.08 (m, 1H),4.23-4.45 (m, 2H), 5.55-5.61 (t, 1H), 5.85-6.10 (m, 2H), 6.15-6.23 (m,1H), 7.20-7.26 (m, 2H), 7.43-7.46 (m, 2H), 7.54-7.57 (d, 1H), 11.50 (s,1H); MS, m/e 536.1 (M + 1)+ 23 3,4-Cl—Ph H H Me Me 1H NMR (DMSO-d₆) δ1.13 (m, 6H), 3.49 (s, 3H), 3.61-3.85 (m, 2H), 3.90-3.93 (m, 1H),4.16-4.22 (m, 1H), 4.27-4.31 (m, 1H), 5.47-5.52 (m, 1H), 5.82 (d, J =11.6 Hz, 1H), 5.93 (d, J = 19.2 Hz, 1H), 6.15-6.25 (m, 1H), 7.13 (t, J =9.6 Hz, 1H), 7.43 (d, J = 12 Hz, 2H), 7.57 (d, J = 6.0 Hz, 1H), 11.43(s, 1H); MS, m/e 569.85 (M + H)+ 24 Ph H H Me 2-Bu 1H NMR (DMSO-d₆) δ0.83 (d, J = 6.8 Hz, 6H), 1.20-1.26 (m, 6H), 1.79-1.86 (m, 1H),3.73-3.90 (m, 4H), 4.01 (t, J = 11.2 Hz, 1H), 4.21- 4.28 (m, 1H),4.33-4.42 (m, 1H), 5.54 (t, J = 7.6 Hz, 1H), 5.85-5.92 (m, 1H),5.99-6.13 (m, 2H), 7.19 (t, J = 8 Hz, 3H), 7.36 (t, J = 7.6 Hz, 2H),7.53 (d, J = 7.6 Hz, 1H), 11.52 (s, 1H); MS, m/e 544.00 (M + 1)+ 25 Ph HH Me i-Pr 1H NMR (DMSO-d₆) δ 1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H),3.95- 4.08 (m, 1H), 4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m,1H), 5.84-6.15 (m, 3H), 7.17-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57(m, 1H), 11.50 (s, 1H); MS, m/e 530.2 (M + 1)+ 26 4-MeO—Ph H H Me n-Bu1HNMR (400 MHz, DMSO-d₆): δ = 0.78-0.82 (m, 3H), 1.29-1.47 (m, 8H),1.49-1.54 (m, 2H), 3.66-3.87 (m, 5H), 3.96-4.02 (m, 3H), 4.21- 4.39 (m,2H), 5.57 (t, J = 12.0 Hz, 1H), 5.84-6.05 (m, 3H), 6.90 (dd, J1 = 8.0Hz, J2 = 4.0 Hz, 2H), 7.09-7.14 (dd, J1 = 16.0 Hz, J2 = 4.0 Hz, 2H),7.55 (d, J = 8.0 Hz, 1H), 11.48-11.62 (s, 1H) 27 4-F—Ph H H Me Et 1H NMR(DMSO-d₆) δ 1.12-1.28 (m, 9H), 3.72-3.94 (m, 2H), 3.98-4.10 (m, 3H),4.21-4.42 (m, 2H), 5.55-5.61 (t, 1H), 5.85-6.20 (m, 3H), 7.18- 7.25 (m,4H), 7.55-7.58 (d, 1H), 11.50 (s, 1H); MS, m/e 533.90 (M + 1)+ 28 4-F—PhH H Me i-Pr 1H NMR (DMSO-d₆) δ 1.13-1.30 (m, 12H), 3.74-3.85 (m, 2H),3.98- 4.06 (m, 1H), 4.23-4.41 (m, 2H), 4.83-4.87 (m, 1H), 5.55-5.61 (t,1H), 5.85-6.12 (m, 3H), 7.18-7.24 (m, 4H), 7.55-7.58 (d, 1H), 11.50 (s,1H); MS, m/e 547.91 (M + 1)+ 29 4-F—Ph H H Me Bn 1H NMR (DMSO-d₆) δ1.10-1.23 (m, 6H), 3.65-3.89 (m, 3H), 4.10-4.30 (m, 2H), 4.96-5.00 (m,2H), 5.46-5.50 (t, 1H), 5.75-5.96 (m, 2H), 6.04- 6.12 (m, 1H), 7.05-7.11(m, 4H), 7.20-7.24 (d, 5H), 7.42-7.45 (d, 1H), 11.50 (s, 1H); MS, m/e595.94 (M + 1)+ 30 4-MeO—Ph H H Me i-Pr 1HNMR (400 MHz, DMSO-d₆): δ =1.15-1.27 (m, 12H), 3.71-3.89 (m, 5H), 3.98-4.02 (m, 1H), 4.22-4.25 (m,1H), 4.33-4.39 (m, 1H), 4.84- 4.87 (m, 1H), 5.57 (t, J = 12.0 Hz, 1H),5.91-6.03 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 7.09-7.14 (m, 2H), 7.55 (d,J = 8.0 Hz, 1H), 11.51 (s, 1H) 31 2-Cl—Ph H H Me Bn 1H NMR (DMSO-d₆) δ1.23 (m, 6 H), 3.93-4.00 (m, 3 H), 4.27-4.40 (m, 2H), 5.0 (t, J = 7.2Hz, 2 H), 5.53 (m, 1 H), 5.80-6.0 (m, 2 H), 6.30 (m, 1H), 7.15 (d, J =2.4 Hz, 1 H), 7.27 (m, 6 H), 7.51 (m, 3 H), 11.5 (s, 1 H); MS, m/e579.87 (M + 1)+/596.78 (M + 18)+ 32 2,4-Cl—Ph H H Me n-Bu 1H NMR(DMSO-d₆) δ = 0.82 (m, 3 H), 1.23 (m, 8 H), 1.47 (m, 2 H), 3.86 (m, 2H), 3.84 (m, 3 H), 4.27-4.43 (m, 2H), 5.5 (m, 1 H), 6.02 (m, 2 H), 6.35(m, 1H), 7.44 (m, 3 H), 7.77 (m, 1 H), 11.5 (s, 1 H); MS, m/e 611.87(M + 1)+ 33 4-Me—Ph H H Me i-Pr 1H NMR (DMSO-d₆) δ 1.14-1.27 (m, 12H),2.17-2.26 (m, 3H), 3.73- 3.82 (m, 1H), 3.99-4.02 (m, 1H), 4.23-4.26 (m,1H), 4.37-4.40 (m, 1H), 4.82-4.88 (m, 1H), 5.52-5.58 (m, 1H), 5.85-6.07(m, 3H), 7.01- 7.20 (m, 4H), 7.55 (d, J = 16 Hz, 1H), 11.51 (s, 1H); MS,m/e 543.98 (M + 1)+; 1108.86 (2M + 23)+ 34 4-F—Ph H H Me n-Bu 1H NMR(DMSO-d₆) δ 0.82-0.89 (m, 3H), 1.20-1.31 (m, 8H), 1.48- 1.53 (m, 2H),3.77-3.90 (m, 2H), 3.95-4.10 (m, 3H), 4.21-4.45 (m, 2H), 5.56-5.61 (t,1H), 5.83-6.20 (m, 3H), 7.18-7.25 (m, 4H), 7.55-7.58 (d, 1H), 11.50 (s,1H); MS, m/e 584.1 (M + 23)+ 35 3,4-diCl—Ph H H Me Et 1H NMR (DMSO-d₆) δ1.12-1.31 (m, 9H), 3.77-3.92 (m, 2H), 3.95-4.08 (m, 3H), 4.21-4.45 (m,2H), 5.56-5.62 (t, 1H), 5.80-6.11 (m, 2H), 6.18- 6.33 (m, 1H), 7.18-7.25(m, 1H), 7.49-7.56 (d, 2H), 7.62-7.67 (m, 1H), 11.50 (s, 1H); MS, m/e606.1 (M + 23)+ 36 2-Cl—Ph H H Me i-Pr 1HNMR (400 MHz, DMSO-d₆): δ =1.12-1.16 (m, 6H), 1.21-1.27 (m, 6H), 3.79-3.85 (m, 2H), 4.00-4.07 (m,1H), 4.28-4.32 (m, 1H), 4.38- 4.43 (m, 1H), 4.83-4.87 (m, 1H), 5.56 (dd,J1 = 16.0 Hz, J2 = 8.0 Hz, 1H), 5.85-6.12 (m, 2H), 6.20-6.33 (m, 1H),7.19-7.22 (m, 1H), 7.33 (t, J = 16.0 Hz, 1H), 7.48-7.55 (m, 3H), 11.55(s, 1H) 37 4-MeO—Ph H H Me Bn 1HNMR (400 MHz, DMSO-d₆): δ = 1.19-1.26(m, 6H), 3.69-3.70 (s, 3H), 3.87 (m, 2H), 3.99 (m, 1H), 4.20-4.21 (m,1H), 4.35 (m, 1H), 5.07-5.09 (m, 2H), 5.54 (t, J = 16.0 Hz, 1H),5.85-5.92 (m, 1H), 6.04- 6.10 (m, 2H), 6.86 (d, J = 8.0 Hz, 2H), 7.09(dd, J1 = 16.0 Hz, J2 = 4.0 Hz, 2H), 7.30-7.34 (m, 5H), 7.53 (s, 1H),11.52 (s, 1H) 38 Ph H H Me n-Pen 1H NMR (DMSO-d₆) δ 0.79-0.81 (m, 3H),1.17-1.23 (m, 10H), 3.74- 3.81 (m, 2H), 3.94-3.96 (m, 3H), 4.19-4.36 (m,2H), 5.49-5.54 (m, 1H), 5.87-6.08 (m, 3H), 7.14-7.33 (m, 3H), 7.31-7.35(m, 2H), 7.51 (d, J = 8 Hz, 1H), 11.51 (s, 1H); MS, m/e 557.9 (M + 1)+;1136.88 (2M + 23)+ 39 4-Cl—Ph H H Me i-Pr 1H NMR (DMSO-d₆) δ 1.04-1.19(m, 12H), 3.76-3.80 (m , 2H), 3.98- 4.08 (m, 1H), 4.42-4.42 (m, 2H),4.82-4.85 (m, 1H), 5.55-5.60 (m, 1H), 5.80-6.20 (m, 3H), 7.20-7.25 (m,2H), 7.43 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8 Hz, 1H), 11.51 (s, 1H);MS, m/e 563.88 (M + 1)+; 1148.73 (2M + 23)+ 40 4-Cl—Ph H H Me n-Bu 1HNMR (DMSO-d₆) δ 0.85 (t, J = 7.2 Hz, 3H), 1.22-1.33 (m, 8H), 1.45-1.53(m, 2H), 3.80-3.87 (m, 2H), 3.96-4.04 (m, 3H), 4.24- 4.27 (m, 1H),4.35-4.39 (m, 1H), 5.56-5.61 (m, 1H), 5.82-6.11 (m, 2H), 6.15-6.18 (m,1H), 7.20-7.56 (m, 4H), 7.51-7.57 (m, 1H), 11.54 (s, 1H); MS, m/e 577.95(M + 1)+ 41 4-Cl—Ph H H Me Et 1H NMR (DMSO-d₆) δ 1.14 (t, J = 7.0 Hz,3H), 1.20-1.28 (m, 6H), 3.77-3.88 (m, 2H), 3.99-4.07 (m, 3H), 4.24-4.28(m, 1H), 4.34- 4.43 (m, 1H), 5.56-5.61 (m, 1H), 5.86-6.13 (m, 2H),6.15-6.24 (m, 1H), 7.20-7.26 (m, 2H), 7.44 (d, J = 7.6 Hz, 2H), 7.55 (d,J = 7.6 Hz, 1H), 11.55 (s, 1H); MS, m/e 549.11 (M + 1)+ 42 4-Me—Ph H HMe n-Bu 1H NMR (DMSO-d₆) δ 0.79-0.83 (m, 3H), 1.17-1.28 (m, 8H), 1.45-1.47 (m, 2H), 2.22 (d, J = 2.8 Hz, 1H), 3.70-3.90 (m, 2H), 3.95-3.98 (m,3H), 4.10-4.40 (m, 2H), 5.51 (t, 1H), 5.80-5.90 (m, 1H), 5.95-6.05 (m,2H), 7.02-7.06 (m, 2H), 7.51 (t, J = 4.2 Hz, 4H), 7.51 (d, 1H), 11.51(s, 1H); MS, m/e 557.99 (M + 1)+; 1136.84 (2M + 23)+ 43 4-Me—Phe H H MeBn 1H NMR (DMSO-d₆) δ 1.16-1.24 (m, 6H), 2.22 (s, 3H), 3.65-4.03 (m,3H), 4.11-4.38 (m, 2H), 5.04-5.05 (m, 2H), 5.48-5.50 (m, 1H), 5.77-5.87(m, 1H), 5.90-6.11 (m, 2H), 6.98-7.10 (m, 4H), 7.28-7.32 (m, 5H), 7.50(t, 1H), 11.48 (s, 1H); MS, m/e 592.00 (M + 1)+. 44 Ph H H Et Me 1H NMR(DMSO-d₆) δ 0.70-0.80 (m, 3H), 1.11-1.26 (m, 3H), 1.42- 1.61 (m, 2H),3.50-3.54 (m, 3H), 3.58-3.80 (m, 2H), 3.91-4.02 (m, 1H), 4.12-4.38 (m,2H), 5.47-5.52 (m, 1H), 5.90-6.03 (m, 2H), 7.08- 7.16 (m, 3H), 7.26-7.35(m, 2H), 7.48 (t, 1H), 11.45 (s, 1H); MS, m/e 515.95 (M + 1)+; 1052.82(2M + 23)+ 45 Ph H H Me 4-F—Bn ¹HNMR (400 MHz, DMSO-d₆): δ 1.20-1.26 (m,6H), 3.80-3.93 (m, 2H), 3.98 (s, 1H), 4.25-4.26 (m, 1H), 4.36-4.37 (m,1H), 5.07 (s, 2H), 5.52-5.55 (m, 1H), 5.86-5.87 (m, 1H), 5.98-6.04 (m,1H), 6.14-6.17 (m, 1H), 7.15-7.20 (m, 5H), 7.36 (dd, J = 20.0, 8.0 Hz,4H), 7.54 (s, 1H), 11.55 (s, 1H) 46 4-Cl—Ph H H Me n-Bu ¹HNMR (400 MHz,DMSO-d₆): δ 1.21-1.28 (m, 6H), 3.71-3.88 (m, 1H), 3.91-3.98 (m, 1H),4.00-4.01 (m, 1H), 4.23-4.27 (m, 1H), 4.35- 4.38 (m, 1H), 5.08 (d, J =4.0 Hz, 2H), 5.57 (dd, J = 12.0, 8.0 Hz, 1H), 5.91 (d, J = 8.0 Hz, 1H),6.01 (d, J = 8.0 Hz, 1H), 6.22-6.24 (m, 1H), 7.17-7.23 (m, 2H),7.31-7.40 (m, 7H), 7.53 (s, 1H), 11.50 (s, 1H) 47 Ph H H Me 3-Me—1-Bu ¹HNMR (DMSO-d₆) δ 0.80-0.82 (m, 6H), 1.18-1.40 (m, 8H), 1.50- 1.58 (m,1H), 3.71-3.82 (m, 3H), 3.97-4.01 (m, 3H), 4.21-4.40 (m, 2H), 5.30 (t, J= 8.6 Hz, 1H), 5.81-6.10 (m, 3H), 7.15-7.20 (m, 3H), 7.32-7.36 (m, 2H),7.48 (d, J = 8.4 Hz, 1H), 11.38 (s, 1H); MS, m/e 557.98 (M + 1)⁺;1136.88 (2M + 23)⁺ 48 3,4-diCl—Ph H H Me Bn ¹H NMR (DMSO-d₆) δ 1.05-1.37(m, 6H), 3.71-3.82 (m, 1H), 3.87- 4.02 (m, 2H), 4.28-4.29 (m, 1H),4.36-4.38 (m, 1H), 5.04 (d, J = 5.2 Hz, 2H), 5.55-5.64 (m, 1H),5.85-5.94 (m, 1H), 6.00-6.05 (m, 1H), 6.29- 6.40 (m, 1H), 7.17-7.24 (m,1H), 7.30-7.41 (m, 5H), 7.45-7.58 (m, 2H), 7.61 (d, J = 4.0 Hz, 1H),11.53 (s, 1H); MS, m/e 545.80 (M + 1)⁺; 49 Ph H H Me c-Hex ¹H NMR(DMSO-d₆) δ 1.18-1.41 (m, 12H), 1.59-1.67 (m, 4H), 3.74- 13.80 (m, 1H),3.96-4.02 (m, 1H), 4.19-4.26 (m, 1H), 4.31-4.39 (m, 1H), 4.60 (s, 1H),5.52 (t, J = 7.8 Hz, 1H), 5.80-6.09 (m, 3H), 7.15- 7.20 (m, 3H),7.32-7.36 (m, 2H), 7.52 (d, J = 8 Hz, 1H), 11.50 (s, 1H); MS, m/e 569.98(M + 1)⁺; 592.14 (M + 23)⁺ 50 Ph H Me H n-Bu 1H NMR (DMSO-d₆) δ 0.76 (t,J = 7.2 Hz, 3H), 1.10-1.22 (m, 8H), 1.38-1.43 (m, 2H), 3.72-3.75 (m,2H), 3.87-3.93 (m, 3H), 4.14-4.21 (m, 1H), 4.23-4.33 (m, 1H), 5.46-5.54(m, 1H), 5.84-6.11 (m, 3H), 7.09-7.14 (m, 2H), 7.27-7.32 (m, 2H),7.34-7.51 (m, 1H), 11.47 (s, 1H); MS, m/e 543.98 (M + 1)+ 51 Ph H Me Hi-Pr 1H NMR (DMSO-d₆) δ 1.39 (d, J = 7.2 Hz, 6H), 1.19-1.29 (m, 6H),3.65-3.75 (m, 2H), 3.95-4.05 (m, 1H), 4.20-4.22 (m, 1H), 4.31-4.33 (m,1H), 4.79-4.82 (m, 1H), 5.48-5.57 (m, 1H), 5.84-5.91 (m, 1H), 5.96-6.07(m, 2H), 7.12-7.35 (m, 5H), 7.44-7.54 (m, 1H), 11.49 (s, 1H); MS, m/e529.96 (M + 1)+ 52 Ph H Me H Bn ¹H NMR (DMSO-d₆) δ 1.18-1.28 (m, 6H),3.70-3.83 (m, 1H), 3.87- 3.94 (m, 1H), 3.99-4.01 (m, 1H), 4.23-4.26 (m,1H), 4.33-4.37 (m, 1H), 5.03-5.12 (m, 2H), 5.51-5.59 (m, 1H), 5.87-5.90(m, 1H), 5.95- 6.07 (m, 1H), 6.10-6.27 (m, 1H), 7.15-7.23 (m, 3H),7.31-7.38 (m, 7H), 7.47-7.56 (m, 1H), 11.50 (s, 1H); MS, m/e 577.99 (M +1)+ 53 2-Cl—Ph H H Me n-Bu ¹HNMR (400 MHz, DMSO-d₆): δ 0.81-0.86 (m,3H), 1.21-1.31 (m, 8H), 1.46-1.52 (m, 2H), 3.84-3.90 (m, 2H), 3.97-4.04(m, 3H), 4.27- 4.41 (m, 2H), 5.53-5.58 (m, 1H), 5.82-5.95 (m, 1H),5.96-6.10 (m, 1H), 6.27-6.31 (m, 1H), 7.19-7.22 (m, 1H), 7.34 (dd, J =8.0, 4.0 Hz, 1H), 7.47-7.55 (m, 3H), 11.55 (s, 1H) 54 4-Br—Ph H H Mei-Pr ¹HNMR (400 MHz, DMSO-d₆): δ 1.10-1.14 (m, 6H), 1.20-1.27 (m, 6H),3.74-3.81 (m, 2H), 3.99-4.01 (m, 1H), 4.21-4.25 (m, 1H), 4.37- 4.38 (m,1H), 4.81-4.85 (m, 1H), 5.58 (dd, J = 8.0, 4.0 Hz, 1H), 5.82- 5.95 (m,1H), 5.96-6.09 (m, 1H), 6.10-6.13 (m, 1H), 7.18 (dd, J = 12.0, 8.0 Hz,2H), 7.53-7.57 (m, 3H), 11.52 (s, 1H) 55 4-F—Ph H H Me c-Hex ¹H NMR(DMSO-d₆) δ 1.20-1.44 (m, 12H), 1.60-1.71 (m, 4H), 3.75- 4.02 (m, 2H),3.94-4.02 (m, 1H), 4.19-4.26 (m, 2H), 4.59-4.61 (m, 1H), 5.57 (t, J =8.4 Hz, 1H), 5.85-6.06 (m, 3H), 7.17-7.23 (m, 4H), 7.54 (d, J = 8.4 Hz,1H), 11.50 (s, 1H); MS, m/e 587.92 (M + 1)⁺ 56 4-Br—Ph H H Me c-Hex¹HNMR (400 MHz, DMSO-d₆): δ = 1.18-1.46 (m, 12H), 1.61-1.69 (m, 4H),3.75-3.82 (m, 2H), 3.95-4.08 (m, 1H), 4.25-4.28 (m, 1H), 4.38 (s, 1H),4.60-4.62 (m, 1H), 5.56-5.60 (m, 1H), 5.82-5.95 (m, 1H), 6.02- 6.20 (m,2H), 7.09-7.20 (m, 2H), 7.53-7.57 (m, 3H), 11.52 (s, 1H) MS m/e 650.0(M + 3)⁺ 57 Ph H H Et i-Pr ¹HNMR (400 MHz, DMSO-d₆): δ = 0.75-0.82 (m,3H), 1.12-1.26 (m, 9H), 1.52-1.59 (m, 2H), 3.55-3.68 (m, 1H), 3.72-3.85(m, 1H), 3.95- 4.08 (m, 1H), 4.18-4.28 (m, 1H), 4.32-4.41 (m, 1H),4.83-4.86 (m, 1H), 5.55 (m, J = 7.6 Hz, 1H), 5.99-6.04 (m, 2H),6.05-6.10 (m, 1H), 7.14-7.21 (m, 3H), 7.33-7.37 (m, 2H), 7.52-7.54 (m,1H), 11.53 (s, 1H); MS, m/e 566.07 (M + 23)⁺ 58 Ph H H Et c-Hex ¹HNMR(400 MHz, DMSO-d₆): δ 0.75-0.88 (m, 3H), 1.26-1.46 (m, 9H), 1.52-1.69(m, 6H), 3.60-3.63 (m, 1H), 3.72-3.90 (m, 1H), 4.02- 4.03 (m, 1H),4.24-4.27 (m, 1H), 4.37-4.38 (m, 1H), 4.63-4.65 (m, 1H), 5.55 (dd, J =8.0 Hz, 4.4 Hz, 1H), 5.80-5.95 (m, 1H), 6.00-6.07 (m, 2H), 7.15-7.22 (m,3H), 7.34-7.38 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 11.55 (s, 1H); MS, m/e584.01 (M + 1)⁺, 606.17 (M + 23)⁺ 59 4-F—Ph H H Et c-Hex ¹H NMR(DMSO-d₆) δ 0.75-0.84 (m, 3H), 1.24 (d, J = 22.8 Hz, 3H), 1.29-1.47 (m,6H), 1.51-1.70 (m, 6H), 3.59-3.66 (m, 1H), 3.77-3.84 (m, 1H), 3.98-4.04(m, 1H), 4.21-4.27 (m, 1H), 4.34-4.41 (m, 1H), 4.60-4.65 (m, 1H),5.56-5.60 (m, 1H), 5.84-5.90 (m, 1H), 6.00-6.08 (m, 2H), 7.20-7.24 (m,4H), 7.56 (d, J = 8.0 Hz, 1H), 11.49 (s, 1H); MS, m/e 602.00 (M + 1)⁺ 60Ph H H Me F—CH₂—CH₂— ¹H NMR (DMSO-d₆) δ 1.18-1.25 (m, 6H), 3.71-3.89 (m,2H), 3.92-3.99 (m, 1H), 4.19-4.27 (m, 4H), 4.48-4.61 (m, 2H), 3.94-3.98(m, 2H), 4.11-4.23 (m, 4H), 5.47-5.52 (m, 1H), 6.01-6.11 (m, 1H),5.90-6.14 (m, 2H), 7.15-7.21 (m, 3H), 7.32-7.36 (m, 2H), 7.46-7.57 (m,1H), 11.49 (s, 1H); MS, m/e 533.86 (M + 1)⁺ 61 Ph H H Me F₂CH—CH₂— ¹HNMR (DMSO-d₆) δ 1.17-1.24 (m, 6H), 3.67-3.81 (m, 1H), 3.89- 3.98 (m,2H), 4.21-4.36 (m, 4H), 5.48-5.53 (m, 1H), 5.82-6.05 (m, 2H), 6.18-6.22(m, 2H), 7.15-7.20 (m, 3H), 7.32-7.36 (m, 2H), 7.51 (s, 1H), 11.50 (s,1H); MS, m/e 551.92 (M + 1)⁺; 62 Ph H H Me (CF₃)₂—CH— ¹H NMR (DMSO-d₆) δ1.13-1.29 (m, 6H), 3.67-3.81 (m, 1H), 3.94- 4.32 (m, 4H), 5.47 (t, J = 8Hz 1H), 5.82-6.01 (m, 2H), 6.33-6.36 (m, 1H), 6.70-6.78 (m, 1H),7.09-7.15 (m, 3H), 7.28-7.32 (m, 2H), 7.43- 7.46 (m, 1H), 11.44 (s, 1H);MS, m/e 637.90 (M + 1)⁺ 63 Ph H H Me (CH₂F)₂—CH— ¹H NMR (DMSO-d₆) δ1.20-1.29 (m, 6H), 3.70-3.90 (m, 1H), 3.91- 4.12 (m, 2H), 4.20-4.33 (m,1H), 4.35-4.48 (m, 1H), 4.52-4.55 (m, 2H), 4.63-4.67 (m, 2H), 5.20-5.35(m, 1H), 5.56 (t, J = 8.4 Hz, 1H), 5.80-5.95 (m, 1H), 5.95-6.10 (m, 1H),6.18-6.21 (m, 1H), 7.18-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54 (s, 1H),11.55 (s, 1H); MS, m/e 565.98 (M + 1)⁺ 64 Ph H H Me c-Pr—CH₂— ¹H NMR(DMSO-d₆) δ 0.20-0.24 (m, 2H), 0.47-0.48 (m, 2H), 0.76- 0.84 (m, 3H),1.03-1.05 (m, 1H), 1.23 (dd, J = 22.4 6.8 Hz 3H), 1.55- 1.60 (m, 2H),3.61-3.68 (m, 1H), 3.81-3.89 (m, 3H), 3.98-4.03 (m, 1H), 4.23-4.29 (m,1H), 4.35-4.41 (m, 1H), 5.56-6.00 (m, 1H), 5.88-5.91 (m, 1H), 6.04-6.10(m, 2H), 7.20-7.24 (m, 4H), 7.55 (d, J = 7.6 Hz 1H), 11.53 (s, 1H); MS,m/e 573.17 (M + 1)⁺ 65 Ph H H Et c-Pen ¹H NMR (DMSO-d₆) δ 0.75-0.83 (m,3H), 1.20-1.28 (m, 3H), 1.49- 1.63 (m, 8H), 1.76-1.80 (m, 2H), 3.58-3.60(m, 1H), 3.70-3.82 (m, 1H), 3.98-4.05 (m, 1H), 4.24-4.26 (m, 1H),4.37-4.42 (m, 1H), 5.03 (s, 1H), 5.54-5.57 (m, 1H), 5.90-6.00 (m, 1H),6.02-6.07 (m, 2H), 7.15- 7.22 (m, 3H), 7.35-7.39 (m, 2H) 7.55 (d, J =8.0 Hz, 1H), 11.55 (s, 1H); MS, m/e 570.03 (M + 1)⁺ *R² and R^(3b)together are —(CH₂)₃— as derived from L-proline

The Purification Procedure by Prep-HPLC:

Crude products were dissolved in methanol. Injection volumes of thesesolutions were 5 mL.

The preparative HPLC system including 2 sets of Gilson 306 pumps, aGilson 156 UV/Vis detector, a Gilson 215 injector & fraction collector,with Unipoint control software. A Ymc 25×30×2 mm column was used. Themobile phase was HPLC grade water (A), and HPLC grade acetonitrile (B).Fractions were collected into 100*15 mm glass tubes.

HPLC gradient is shown in Table 1. Once the gradient was selected,acetonitrile solution was injected into HPLC system, and then fractionscollected according to UV peaks. After the separation, each glass tubeswere run MS test to collect the desired compounds. The fractions withtarget MS were combined in a well-weighted flask. Most of acetonitrilewas removed under reduce pressure and the remaining solution wasfreeze-dried to give desired compound.

TABLE 1 Preparative HPLC gradient Time (min) Flow rate (mL/min) % A % B0 15 90 10 30 15 60 40

Preparation of Example 66

Preparation of Compound (b)

To a solution of compound a (1 g, 2.69 mmol) in anhydrous THF (30 mL)was added dropwise 1 M solution of LiAl(OBu-t)₃H in THF (2.69 mL, 2.69mmol) at −20° C. The reaction mixture was stirred, for 2-3 h at the sametemperature. EtOAc (100 mL) was added followed by saturated NH₄Clsolution (10 mL) and reaction mixture was slowly brought to roomtemperature. Reaction mixture was extracted with EtOAc and washed with1N HCl and water. Combined organic phase was evaporated to give 0.8 g ofcrude compound b as transparent oil, which was used directly for nextreaction.

Preparation of Compound (d)

To a solution of compound b (0.8 g, 2.1 mmol), compound c (0.45 g, 2.5mmol) and Ph₃P (0.56 g, 2.1 mmol) in anhydrous THF (20 mL) undernitrogen atmosphere was added DEAD (1.8 mL). The reaction mixture wasstirred at room temperature overnight. The reaction solution wasconcentrated under reduce pressure. The residue was separated bypreparative layer chromatography (hexanes:EtOAc=3:1) to give crudecompound d (0.8 g). The crude compound d was used to the next stepwithout further purification,

Preparation of Compound (e)

Compound d (0.8 g, 1.57 mmol) was dissolved in THF (2 mL) and THFsaturated with ammonia (5 mL) was then added to this solution. Thereaction mixture was heated to 90° C. overnight. After 18 hours, thesolution was cooled to room temperature by ice water, then the solventwas removed under reduced pressure and the residue was purified bycolumn to give compound e (0.75 g) for the next step.

Preparation of Compound (f)

Compound e (0.5 g, 1.01 mmol) was dissolved in methanol (2 mL) andmethanol was saturated with ammonia (5 mL) was then added to thissolution. The reaction mixture was stirred at room temperatureovernight. After 18 hours, the solvent was removed under reducedpressure and the residue was purified by column to give crude compound f(0.15 g) for the next step.

Preparation of Compound (i)

A solution of triethylamine (1.07 g, 10.6 mmol) in anhydrousdichloromethane (15 mL) was added dropwise to a solution of compound g(1.16 g, 5.3 mmol) and compound h (1.31 g, 5.3 mmol) in dichloromethane(10 mL) with vigorous stirring at −78° C. over a period of 2 hours.After completion of addition, the reaction temperature was allowed towarm to room temperature gradually and stirred over night. Then thesolvent was removed under vacuum and anhydrous ether 20 mL was added andthe precipitated salt was filtered and the precipitate was washed withether. The combined organic phase was concentrated to give the colorlessoil of compound i (1.0 g),

Preparation of Compound 66

To a solution of compound j (0.1 g, 0.35 mmol) dissolved in 10 mL ofanhydrous THF, stirred and added 0.4 g NMI till the solution becameclear, added compound i (0.8 g, 2.89 mmol) in 10 mL THF dropwise,stirred at r.t. overnight. Compound purity and identification wasconfirmed by LCMS. The solvent was evaporated and purified by Prep-HPLCto afford 66. (25 mg, Yield: 13.6%). ¹H NMR (DMSO-d₆) δ 1.08 (d, J=22.8Hz, 3H), 1.17-124 (m, 3H), 3.50-3.52 (m, 3H), 3.78-3.83 (m, 1H),4.10-4.13 (m, 1H), 4.24-4.44 (m, 2H), 5.85-5.92 (m, 1H), 6.01-6.11 (m,1H), 6.2.-6.27 (1H), 7.08-7.19 (m, 4H), 7.31-7.38 (m, 3H), 8.15 (s, 1H),8.26 (s, 1H); MS, m/e 525 (M+1)⁺.

Example numbers 67-74, identified below, were prepared using similarprocedures disclosed for Example 66, above

Example R¹¹ R¹⁰ NMR/MS 67 OH NH₂ ¹H NMR (DMSO-d₆) δ 1.06-1.13 (m, 3H),1.20-1.24 (m, 3H), 3.27-3.33 (m, 3H), 3.56 (s, 1H), 3.82-3.88 (m, 1H),4.07-4.13 (m, 1H), 4.25-4.40 (m, 2H), 5.85-5.87 (m, 1H), 5.98-6.09 (m,2H), 6.59 (s, 32H), 7.14-7.37 (m, 3H), 7.35-7.37 (m, 2H), 7.79 (d, J =7.2 Hz, 1H), 10.69 (s, 1H); MS, m/e 541 (M + 1)⁺; 68 NH₂ NH₂ ¹H NMR(DMSO-d₆) δ 1.07 (d, J = 22.8 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 3.51(s, 3H), 3.62 (s, 1H), 3.75-3.81 (m, 1H), 4.05-4.11 (m, 1H), 4.27-4.42(m, 2H), 5.79-5.83 (m, 1H), 5.92 (s, 2H), 6.00-6.09 (m, 2H), 6.75 (s,2H), 7.08-7.17 (m, 3H), 7.31-7.35 (m, 2H), 7.78 (s, 1H); MS, m/e 540(M + 1)⁺; 69 NH₂ c-Pentyl-NH— ¹H NMR (DMSO-d₆) δ 1.05 (d, J = 22.8 Hz,3H), 1.09-1.19 (m, 3H), 1.48 (s, 4H), 1.66 (s, 1H), 1.86 (s, 1H), 3.54(d, J = 14 Hz, 3H), 3.65 (s, 1H), 4.25-4.43 (m, 4H), 5.71-5.82 (m, 1H),5.94-6.04 (m, 4H), 7.11-7.24 (m, 3H), 7.26-7.34 (m, 2H), 7.77 (d, J =3.6 Hz, 1H); MS, m/e 608 (M + 1)⁺ 70 NH₂

¹H NMR (DMSO-d₆) δ 1.07 (d, J = 22.4 Hz, 3H), 2.35-2.38 (m, 2H), 3.54(d, J = 9.2 Hz, 3H), 3.59-3.62 (m, 2H), 3.65 (s, 1H), 3.75-3.82 (m, 1H),4.01-4.13 (m, 2H), 4.22-4.40 (m, 6H), 5.75-5.85 (m, 1H), 6.00-6.07 (m,4H), 7.15-7.21 (m, 3H), 7.32-7.35 (m, 2H), 7.79 (d, J = 4.0 Hz, 1H); MS,m/e 580 (M + 1)⁺ 71 NH₂ Et₂N— ¹H NMR (DMSO-d₆) δ 1.06-1.28 (m, 12H),3.55 (d, J = 4.8 Hz, 3H), 3.79-3.87 (m, 4H), 4.07-4.12 (m, 2H),4.29-4.42 (m, 3H), 5.75-5.82 (m, 1H), 5.94 (s, 2H), 6.04-6.10 (m, 2H),7.14-7.22 (m, 3H), 7.31-7.37 (m, 2H), 7.82 (d, J = 4.4 Hz, 1H); MS, m/e596 (M + 1)⁺ 72 NH₂ n-Propyl-NH— ¹H NMR (DMSO-d₆) δ 0.84 (t, J = 7.2 Hz,3H), 1.01-1.01 (m, 3H), 1.09-1.12 (m, 3H), 1.51-1.56 (m, 2H), 3.48 (d, J= 15.2 Hz, 3H), 3.79-3.82 (m, 1H), 4.04-4.05 (m, 1H), 4.27-4.38 (m, 3H),5.72-5.79 (m, 1H), 5.98-6.04 (m, 4H), 7.13-7.20 (m, 3H), 7.26-7.32 (m,2H), 7.76 (d, J = 5.2 Hz, 1H); MS, m/e 582 (M + 1)⁺ 73 NH₂ c-Butyl-NH—¹H NMR (DMSO-d₆) δ 1.02-1.08 (m, 3H), 1.18 (d, J = 4.8 Hz, 3H),1.44-1.61 (m, 2H), 2.02-2.17 (m, 4H), 3.51 (d, J = 10.8 Hz, 3H),3.78-3.83 (m, 1H), 4.03-4.06 (m, 1H), 4.27-4.38 (m, 2H), 4.53-4.62 (m,1H), 5.68-5.79 (m, 1H), 5.95-6.04 (m, 4H), 7.11-7.18 (m, 3H), 7.29-7.35(m, 2H), 7.51-7.58 (m, 1H), 7.78 (d, J = 5.2 Hz, 1H); MS, m/e 594 (M +1)⁺ 74 NH₂

¹H NMR (DMSO-d₆) δ 0.97-1.20 (m, 6H), 2.18 (s, 3H), 2.19 (s, 4H),3.43-3.47 (m, 3H), 3.75 (s, 1H), 4.01-4.06 (m, 4 H), 4.22-4.35 (m, 3H),5.69-5.75 (m, 1H), 5.98-6.05 (m, 3H), 7.09-7.15 (m, 3H), 7.25-7.29 (m,2H), 7.77 (d, J = 3.6 Hz, 1H); MS, m/e 623 (M + 1)⁺

Example numbers 75-80 are prepared using similar procedures disclosedfor Example 66, above,

Example R¹¹ R¹⁰ 75 H n-propyl-NH— 76 H c-Butyl-NH— 77 H c-Pentyl-NH— 78H

79 H

80 H

Example 81

Certain exemplified compounds were obtained as mixture of diastereomersbecause of the chirality at phosphorous. The diastereomers wereseparated on a Chiralpak-AS-H (2×25 cm) column under Supercritical FluidChromatography (SFC) conditions using 20% methanol in carbon dioxide assolvent. The absolute stereochemistry of the P-chiral center of thediastereomers were not determined. However, chromatographic resolutionof these two diastereomers provides for isomers that are characterizedas fast eluting and slow eluting isomers. Some examples are shown below.

Compound EC90 (uM) Example 15 (Diastereomeric mixture) 0.86 Fast Movingisomer of Example 15 1.35 Slow Moving isomer of Example 15 0.26 Example39 (Diastereomeric mixture) 0.47 Fast Moving isomer of Example 39 0.78Slow Moving isomer of Example 39 0.02 Example 49 (Diastereomericmixture) 0.126 Fast Moving isomer of Example 49 0.03 Slow Moving isomerof Example 49 5.78

Example 82 HCV Replicon Assay

HCV replicon RNA-containing Huh7 cells (clone A cells; Apath, LLC, St.Louis, Mo.) were kept at exponential growth in Dulbecco's modifiedEagle's medium (high glucose) containing 10% fetal bovine serum, 4 mML-glutamine and 1 mM sodium pyruvate, 1× nonessential amino acids, andG418 (1,000 μg/ml). Antiviral assays were performed in the same mediumwithout G418. Cells were seeded in a 96-well plate at 1,500 cells perwell, and test compounds were added immediately after seeding.Incubation time 4 days. At the end of the incubation step, totalcellular RNA was isolated (RNeasy 96 kit; Qiagen). Replicon RNA and aninternal control (TaqMan rRNA control reagents; Applied Biosystems) wereamplified in a single-step multiplex RT-PCR protocol as recommended bythe manufacturer. The HCV primers and probe were designed with PrimerExpress software (Applied Biosystems) and covered highly conserved5′-untranslated region (UTR) sequences (sense,5′-AGCCATGGCGTTAGTA(T)GAGTGT-3′, and antisense,5′-TTCCGCAGACCACTATGG-3′; probe, 5′-FAM-CCTCCAGGACCCCCCCTCCC-TAMRA-3).

To express the antiviral effectiveness of a compound, the thresholdRT-PCR cycle of the test compound was subtracted from the averagethreshold RT-PCR cycle of the no-drug control (ΔCt_(HCV)). A ΔCt of 3.3equals a 1-log 10 reduction (equal to the 90% effective concentration[EC₉₀]) in replicon RNA levels. The cytotoxicity of the test compoundcould also be expressed by calculating the ΔCt_(rRNA) values. The ΔΔCtspecificity parameter could then be introduced (ΔCt_(HCV)-ΔCt_(rRNA)),in which the levels of HCV RNA are normalized for the rRNA levels andcalibrated against the no-drug control.

Log10 Ex Reduction EC90 # Compound at 50 μM (μM)  5

−1.21  3.0  6

−0.45 ND  7

 0.31 ND  8

−1.48  2.11 10

−1.25 19.15 11

−0.55 ND 12

 0.31 ND 15

ND  0.86 25

−2.22  0.39 27

−2.25  0.66 28

−2.16  0.75 36

−1.64 21.9 39

−1.78  0.47 49

−2.69  0.126 53

−1.33 <0.3 54

−1.55  0.57 55

−2.38 <0.3 69

−2.25 <0.3 70

−2.25 <0.3 ¹(4-BrPh): 4-bromo-phenyl.

The entire contents of U.S. Provisional Application Nos. 60/909,315,filed Mar. 30, 2007, and 60/982,309, filed Oct. 24, 2007, are herebyincorporated by reference in the present application so far as needed tosupplement the present disclosure and/or rectify any errors. Moreover,the patent and non-patent references disclosed herein are incorporatedby reference. In the event that the incorporated patent and non-patentreference contains a term that conflicts with a term disclosed in eitherone of the two Provisional Applications or the present application text,the meaning of the term contained in the present application text andthe two Provisional Applications controls provided that the overallmeaning of the incorporated subject matter is not lost.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20140288020A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

We claim:
 1. A compound, its stereoisomer, salt, hydrate, solvate, orcrystalline form thereof, represented by formula I:

(a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; or aryl, whichincludes, but is not limited to, phenyl or naphthyl, where phenyl ornaphthyl are optionally substituted with at least one of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro, cyano,C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R)₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R^(1′) is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R³)₂); (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyloptionally substituted with a lower alkyl, alkoxy, di(loweralkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,such as, pyridinyl, substituted aryl, or substituted heteroaryl; (e) R⁵is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl,i.e., —(CH₂)_(p)OH, where p is 1-6; including hydroxyl methyl(CH₂OH),CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionallysubstituted), or halogen, including F, Cl, Br, or I, with the provisosthat when X is OH, base is cytosine and R⁶ is H, R⁵ cannot be N₃ andwhen X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H, OH, F, OMe,halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl),OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl),S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O)alkyl, C(O)(C₁₋₂₀ alkyl),C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.
 2. A compound its stereoisomer, salt, hydrate,solvate, or crystalline form thereof selected from among 52′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenyl methoxy-alanylphosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate.
 3. A compositionfor the treatment and/or prophylaxis of any of the viral agentsdisclosed herein said composition comprising a pharmaceuticallyacceptable medium selected from among an excipient, carrier, diluent,and equivalent medium and a compound, its stereoisomer, salt, hydrate,solvate, or crystalline form thereof, represented by formula I:

wherein (a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; oraryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl are optionally substituted with at least one of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro,cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂); (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyloptionally substituted with a lower alkyl, alkoxy, di(loweralkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,such as, pyridinyl, substituted aryl, or substituted heteroaryl; (e) R⁵is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl,i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxyl methyl(CH₂OH),CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionallysubstituted), or halogen, including F, Cl, Br, or I, with the provisosthat when X is OH, base is cytosine and R⁶ is H, R⁵ cannot be N₃ andwhen X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H, OH, F, OMe,halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl),OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl),S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O)alkyl, C(O)(C₁₋₂₀ alkyl),C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.
 4. A composition for the treatment and/orprophylaxis of any of the viral agents disclosed herein said compositioncomprising a pharmaceutically acceptable medium selected from among anexcipient, carrier, diluent, and equivalent medium and a compound, itsstereoisomer, salt, hydrate, solvate, or crystalline form thereof,selected from among 5 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-alanyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate.5. A use of the compound represented by formula I in the manufacture ofa medicament for the treatment of any condition the result of aninfection by hepatitis C virus, West Nile virus, yellow fever virus,dengue virus, rhinovirus, polio virus, hepatitis A virus, bovine viraldiarrhea virus or Japanese encephalitis virus. wherein the compound, itsstereoisomer, salt, hydrate, solvate, or crystalline form thereof, arerepresented by formula I:

wherein (a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; oraryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl are optionally substituted with at least one of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro,cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R³ is independently hydrogen orC₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂); (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyloptionally substituted with a lower alkyl, alkoxy, di(loweralkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,such as, pyridinyl, substituted aryl, or substituted heteroaryl; (e) R⁵is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl,i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxyl methyl(CH₂OH),CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionallysubstituted), or halogen, including F, Cl, Br, or I, with the provisosthat when X is OH, base is cytosine and R⁶ is H, R⁵ cannot be N₃ andwhen X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H, OH, F, OMe,halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl),OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl),S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O)alkyl, C(O)(C₁₋₂₀ alkyl),C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.
 6. A use of a compound, its stereoisomer, salt,hydrate, solvate, or crystalline form thereof, selected from among 52′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenyl methoxy-alanylphosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2Hpyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino)propanoate in themanufacture of a medicament for the treatment of any condition theresult of an infection by hepatitis C virus, West Nile virus, yellowfever virus, dengue virus, rhinovirus, polio virus, hepatitis A virus,bovine viral diarrhea virus or Japanese encephalitis virus.
 7. A methodof treatment in a subject in need thereof, which comprises:administering a therapeutically effective amount of the compoundrepresented by formula I to the subject; wherein the compound or itsstereoisomer, salt, hydrate, solvate, or crystalline form thereofrepresented by formula I:

wherein (a) R′ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; oraryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl are optionally substituted with at least one of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro,cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂Cl₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR¹, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R³)₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂); (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyloptionally substituted with a lower alkyl, alkoxy, di(loweralkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,such as, pyridinyl, substituted aryl, or substituted heteroaryl; (e) R⁵is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl,i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxyl methyl(CH₂OH),CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionallysubstituted), or halogen, including F, Cl, Br, or I, with the provisosthat when X is OH, base is cytosine and R⁶ is H, R⁵ cannot be N₃ andwhen X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H, OH, F, OMe,halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl),OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl),S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₂₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R′, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O)alkyl, C(O)(C₁₋₂₀ alkyl),C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂.
 8. A method of treatment in a subject in needthereof, which comprises: administering a therapeutically effectiveamount of a compound, its stereoisomer, salt, hydrate, solvate, orcrystalline form thereof, selected from among 52′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenyl methoxy-alanylphosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate.9. A process for preparing a compound, its stereoisomer, salt, hydrate,solvate, or crystalline form thereof, represented by formula I:

wherein (a) R¹ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; oraryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl are optionally substituted with at least one of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro,cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR′, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl; or (viii)R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂, CH₂-imidazol-4-yl,CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lower cycloalkyl and R^(3b)is H, where R^(3′) is independently hydrogen or alkyl, which includes,but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(3″)is —OR′ or —N(R^(3′))₂); (d) R⁴ is hydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkyloptionally substituted with a lower alkyl, alkoxy, di(loweralkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl, heteroaryl,such as, pyridinyl, substituted aryl, or substituted heteroaryl; (e) R⁵is H, a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl,i.e., —(CH₂)_(p)OH, where p is 1-6, including hydroxyl methyl(CH₂OH),CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂, alkyne (optionallysubstituted), or halogen, including F, Cl, Br, or I, with the provisosthat when X is OH, base is cytosine and R⁶ is H, R⁵ cannot be N₃ andwhen X is OH, R⁶ is CH₃ or CH₂F and B is a purine base, R⁵ cannot be H;(f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H, OH, F, OMe,halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄ alkyl),OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl), OC₁₋₁₀haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄ alkenyl),S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl), SO(C₁₋₄acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl), SO₂(C₁₋₄acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₁₈ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O) alkyl, C(O)(C₁₋₂₀alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂; said process comprising: reacting a substitutedphosphochloridate compound 4 with a nucleoside analog 5


10. A process for preparing a compound, its stereoisomer, salt, hydrate,solvate, or crystalline form thereof, selected from among 52′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenyl methoxy-alanylphosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate; 79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate said processcomprising: reacting a substituted phosphochloridate compound 4 with anucleoside analog 5


11. A product its stereoisomer, salt, hydrate, solvate or crystallineform thereof, prepared a process comprising: reacting a substitutedphosphochloridate compound 4 with a nucleoside analog 5

wherein (a) R′ is hydrogen, n-alkyl; branched alkyl; cycloalkyl; oraryl, which includes, but is not limited to, phenyl or naphthyl, wherephenyl or naphthyl are optionally substituted with at least one of C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, F, Cl, Br, I, nitro,cyano, C₁₋₆ haloalkyl, —N(R^(1′))₂, C₁₋₆ acylamino, —NHSO₂C₁₋₆ alkyl,—SO₂N(R^(1′))₂, COR^(1″), and —SO₂C₁₋₆ alkyl; (R′ is independentlyhydrogen or alkyl, which includes, but is not limited to, C₁₋₂₀ alkyl,C₁₋₁₀ alkyl, or C₁₋₆ alkyl, R^(1″) is —OR′ or —N(R^(1′))₂); (b) R² ishydrogen, C₁₋₁₀ alkyl, R^(3a) or R^(3b) and R² together are (CH₂)_(n) soas to form a cyclic ring that includes the adjoining N and C atoms,C(O)CR^(3a)R^(3b)NHR′, where n is 2 to 4 and R¹, R^(3a), and R^(3b); (c)R^(3a) and R^(3b) are (i) independently selected from hydrogen, C₁₋₁₀alkyl, cycloalkyl, —(CH₂)_(c)(NR^(3′))₂, C₁₋₆ hydroxyalkyl, —CH₂SH,—(CH₂)₂S(O)_(d)Me, —(CH₂)₃NHC(═NH)NH₂, (1H-indol-3-yl)methyl,(1H-imidazol-4-yl)methyl, —(CH₂)_(e)COR^(3″), aryl and aryl C₁₋₃ alkyl,said aryl groups optionally substituted with a group selected fromhydroxyl, C₁₋₁₀ alkyl, C₁₋₆ alkoxy, halogen, nitro and cyano; (ii)R^(3a) and R^(3b) both are C₁₋₆ alkyl; (iii) R^(3a) and R^(3b) togetherare (CH₂)_(f) so as to form a spiro ring; (iv) R^(3a) is hydrogen andR^(3b) and R² together are (CH₂)_(n) so as to form a cyclic ring thatincludes the adjoining N and C atoms (v) R^(3b) is hydrogen and R^(3a)and R² together are (CH₂)_(n) so as to form a cyclic ring that includesthe adjoining N and C atoms, where c is 1 to 6, d is 0 to 2, e is 0 to3, f is 2 to 5, n is 2 to 4, and where R^(3′) is independently hydrogenor C₁₋₆ alkyl and R^(3″) is —OR′ or —N(R^(3′))₂); (vi) R^(3a) is H andR^(3b) is H, CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂Ph,CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂, CH₂CH₂COOH,CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CHz₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl; or (viii) R^(3a) is CH₃, —CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂,CH(CH₃)CH₂CH₃, CH₂Ph, CH₂-indol-3-yl, —CH₂CH₂SCH₃, CH₂CO₂H, CH₂C(O)NH₂,CH₂CH₂COOH, CH₂CH₂C(O)NH₂, CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂NHC(NH)NH₂,CH₂-imidazol-4-yl, CH₂OH, CH(OH)CH₃, CH₂((4′-OH)-Ph), CH₂SH, or lowercycloalkyl and R^(3b) is H, where R^(3′) is independently hydrogen oralkyl, which includes, but is not limited to, C₁₋₂₀ alkyl, C₁₋₁₀ alkyl,or C₁₋₆ alkyl, R^(3″) is —OR′ or —N(R)₂); (d) R⁴ is hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ alkyl optionally substituted with a lower alkyl, alkoxy,di(lower alkyl)-amino, or halogen, C₁₋₁₀ haloalkyl, C₃₋₁₀ cycloalkyl,cycloalkyl alkyl, cycloheteroalkyl, aminoacyl, aryl, such as phenyl,heteroaryl, such as, pyridinyl, substituted aryl, or substitutedheteroaryl; (e) R⁵ is H, a lower alkyl, CN, vinyl, O-(lower alkyl),hydroxyl lower alkyl, i.e., —(CH₂)_(p)OH, where p is 1-6, includinghydroxyl methyl(CH₂OH), CH₂F, N₃, CH₂CN, CH₂NH₂, CH₂NHCH₃, CH₂N(CH₃)₂,alkyne (optionally substituted), or halogen, including F, Cl, Br, or I,with the provisos that when X is OH, base is cytosine and R⁶ is H, R⁵cannot be N₃ and when X is OH, R⁶ is CH₃ or CH₂F and B is a purine base,R⁵ cannot be H; (f) R⁶ is H, CH₃, CH₂F, CHF₂, CF₃, F, or CN; (g) X is H,OH, F, OMe, halogen, NH₂, or N₃; (h) Y is OH, H, C₁₋₄ alkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, vinyl, N₃, CN, Cl, Br, F, I, NO₂, OC(O)O(C₁₋₄alkyl), OC(O)O(C₁₋₄ alkyl), OC(O)O(C₂₋₄ alkynyl), OC(O)O(C₂₋₄ alkenyl),OC₁₋₁₀ haloalkyl, O(aminoacyl), O(C₁₋₁₀ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₁₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C1-s₁ acyl)₂, wherein alkyl, alkynyl, alkenyl andvinyl are optionally substituted by N₃, CN, one to three halogen (Cl,Br, F, I), NO₂, C(O)O(C₁₋₄ alkyl), C(O)O(C₁₋₄ alkyl), C(O)O(C₂₋₄alkynyl), C(O)O(C₂₋₄ alkenyl), O(C₁₋₄ acyl), O(C₁₋₄ alkyl), O(C₂₋₄alkenyl), S(C₁₋₄ acyl), S(C₁₋₄ alkyl), S(C₂₋₄ alkynyl), S(C₂₋₄ alkenyl),SO(C₁₋₄ acyl), SO(C₁₋₄ alkyl), SO(C₂₋₄ alkynyl), SO(C₂₋₄ alkenyl),SO₂(C₁₋₄ acyl), SO₂(C₁₋₄ alkyl), SO₂(C₂₋₄ alkynyl), SO₂(C₂₋₄ alkenyl),OS(O)₂(C₁₋₄ acyl), OS(O)₂(C₁₋₄ alkyl), OS(O)₂(C₂₋₄ alkenyl), NH₂,NH(C₁₋₄ alkyl), NH(C₂₋₄ alkenyl), NH(C₂₋₄ alkynyl), NH(C₁₋₄ acyl),N(C₁₋₄ alkyl)₂, N(C₁₋₄ acyl)₂; the base is a naturally occurring ormodified purine or pyrimidine base represented by the followingstructures:

wherein Z is N or CR¹²; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently H, F,Cl, Br, I, OH, OR′, SH, SR′, NH₂, NHR′, NR′₂, lower alkyl of C₁-C₆,halogenated (F, Cl, Br, I) lower alkyl of C₁-C₆, lower alkenyl of C₂-C₆,halogenated (F, Cl, Br, I) lower alkenyl of C₂-C₆, lower alkynyl ofC₂-C₆ such as C≡CH, halogenated (F, Cl, Br, I) lower alkynyl of C₂-C₆,lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I) lower alkoxy of C₁-C₆,CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, or CH═CHCO₂R′, wherein R′is an optionally substituted alkyl, which includes, but is not limitedto, an optionally substituted C₁₋₂₀ alkyl, an optionally substitutedC₁₋₁₀ alkyl, an optionally substituted lower alkyl; an optionallysubstituted cycloalkyl; an optionally substituted alkynyl of C₂-C₆, anoptionally substituted lower alkenyl of C₂-C₆, or optionally substitutedacyl, which includes but is not limited to C(O) alkyl, C(O)(C₁₋₂₀alkyl), C(O)(C₁₋₁₀ alkyl), or C(O)(lower alkyl) or alternatively, in theinstance of NR′₂, each R′comprise at least one C atom that are joined toform a heterocycle comprising at least two carbon atoms; and R¹² is anH, halogen (including F, Cl, Br, I), OH, OR′, SH, SR′, NH₂, NHR′, NR′₂,NO₂ lower alkyl of C₁-C₆, halogenated (F, Cl, Br, I) lower alkyl ofC₁-C₆, lower alkenyl of C₂-C₆, halogenated (F, Cl, Br, I) lower alkenylof C₂-C₆, lower alkynyl of C₂-C₆, halogenated (F, Cl, Br, I) loweralkynyl of C₂-C₆, lower alkoxy of C₁-C₆, halogenated (F, Cl, Br, I)lower alkoxy of C₁-C₆, CO₂H, CO₂R′, CONH₂, CONHR′, CONR′₂, CH═CHCO₂H, orCH═CHCO₂R′; with the proviso that when base is represented by thestructure c with R¹¹ being hydrogen, R¹² is not a: (i) —C≡C—H, (ii)—C═CH₂, or (iii) —NO₂ and wherein X′ is a leaving group, such as, Cl.12. A product its stereoisomer, salt, hydrate, solvate or crystallineform thereof, prepared a process comprising: reacting a substitutedphosphochloridate compound 4 with a nucleoside analog 5

wherein the product comprises a compound, its stereoisomer, salt,hydrate, solvate, or crystalline form thereof, selected from among 52′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenyl methoxy-alanylphosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester); 6 2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 7 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-valyl phosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 8 2′-Deoxy-2′-fluoro-2′-C-methyluridine5′-(4-bromophenyl methoxy-alanyl phosphate(((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester); 9N⁴—(N,N-dimethylformamidinyl)-2′-deoxy-2′-fluoro-2′-C-methylcytidine; 102′-Deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenyl methoxy-alanylphosphate(((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenyoxy-phosphorylamino}-propionicacid methyl ester); 11 2′-Deoxy-2′-fluoro-2′-C-methylcytidine5′-(4-bromophenyl methoxy-valyl phosphate(2′-Deoxy-2′-fluoro-2′-C-methyluridine 5′-(4-bromophenyl methoxy-valylphosphate((S)-2-{(4-bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-3-methyl-butyricacid methyl ester); 12 2′-deoxy-2′-fluoro-2′-C-methylcytidine 5′-(phenylmethoxy-valyl phosphate((S)-2-{[(2R,3R,4R,5R)-5-(2-oxo-3-amino-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-3-methyl-butyricacid methyl ester; 13(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid ethyl ester; 14(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid benzyl ester; 15{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-aceticacid methyl ester; 16(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 17(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionicacid methyl ester; 18(S)-1-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphoryl}-pyrrolidine-2-carboxylicacid methyl ester; 19(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 20(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 21(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid methyl ester; 22(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 23(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid methyl ester; 24(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid sec-butyl ester; 25(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 26(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid butyl ester; 27(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid ethyl ester; 28(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 29(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 30(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid isopropyl ester; 31(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid benzyl ester; 32(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 33(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid isopropyl ester; 34(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid butyl ester; 35(S)-2-{(3,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 36(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 37(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-methoxy-phenoxy)-phosphorylamino]-propionicacid benzyl ester; 38(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid pentyl ester; 39(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 40(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 41(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 42(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid butyl ester; 43(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-p-tolyloxy-phosphorylamino}-propionicacid benzyl ester; 44(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid methyl ester; 45(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 4-fluoro-benzyl ester; 46(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 47(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 3-methyl-butyl ester; 48(S)-2-{(2,4-Dichloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid ethyl ester; 49(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclohexyl ester; 50(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid butyl ester; 51(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid isopropyl ester; 52(R)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid benzyl ester; 53(S)-2-{(2-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid butyl ester; 54(S)-2-{(4-Bromo-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-propionicacid isopropyl ester; 55(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 56(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-bromo-phenoxy)-phosphorylamino]-propionicacid cyclohexyl ester; 57(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid isopropyl ester; 58(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclohexyl ester; 59(S)-2-[[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(4-fluoro-phenoxy)-phosphorylamino]-butyricacid cyclohexyl ester; 60(S)-2-{(4-Chloro-phenoxy)-[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phosphorylamino}-butyricacid isopropyl ester; 61(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2-difluoro-ethyl ester; 62(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 63(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid 2-fluoro-1-fluoromethyl-ethyl ester; 64(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid cyclopropyl methyl ester; 65(S)-2-{[(2R,3R,4R,5R)-5-(2,4-Dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-butyricacid cyclopentyl ester; 66(S)-2-{[(2R,3R,4R,5R)-5-(6-Amino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 67(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-hydroxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 68(S)-2-{(R)-[(2R,3R,4R,5R)-5-(2,6-Diamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 69(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclopentylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 70(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-azetidin-1-yl-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 71(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-diethylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 72(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-propylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 73(S)-2-{[(2R,3R,4R,5R)-5-(2-Amino-6-cyclobutylamino-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionicacid methyl ester; 74(S)-2-({(2R,3R,4R,5R)-5-[2-Amino-6-(4-methyl-piperazin-1-yl)-purin-9-yl]-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy}-phenoxy-phosphorylamino)-propionicacid methyl ester; 75 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(propylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;76 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclobutylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;77 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;78 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(aziridin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;79 (2S)-methyl2-((((2R,3R,4R,5R)-4-fluoro-3-hydroxy-4-methyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;and 80 (2S)-methyl2-((((2R,3R,4R,5R)-5-(6-(azetidin-1-yl)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoatewherein Base′ is as recited in each of compounds 5-74; and wherein X′ isa leaving group, such as, Cl.